Ion binding compositions

ABSTRACT

The present invention provides methods and compositions for the treatment of ion imbalances. In particular, the invention provides core-shell compositions and pharmaceutical compositions thereof. Methods of use of the core-shell compositions for therapeutic and/or prophylactic benefits are disclosed herein. Examples of these methods include the treatment of phosphate imbalance disorders, hypertension, chronic heart failure, end stage renal disease, liver cirrhosis, chronic renal insufficiency, fluid overload, or sodium overload.

CROSS-REFERENCE

This application is a continuation-in-part of U.S. application Ser. No.10/965,274, filed Oct. 13, 2004 which is a continuation-in-partapplication of U.S. application Ser. No. 10/814,527, filed Mar. 30,2004; U.S. application Ser. No. 10/814,749, filed Mar. 30, 2004; andU.S. application Ser. No. 10/813,872, filed Mar. 30, 2004 which areincorporated herein by reference in their entirety.

INTRODUCTION

Ion selective sorbents have been used in human therapy to correctdisorders in electrolyte balance, in conditions such ashyperphosphatemia, hyperoxaluria, hypercalcemia, and hyperkalemia.Hyperphosphatemia occurs in patients with renal failure, whose kidneysno longer excrete enough phosphate ions to compensate exogenousphosphate uptake in the diet. This condition leads to high serumphosphate concentration and high calcium x phosphate product. Althoughthe etiology is not fully demonstrated, high calcium x phosphate producthas been held responsible for soft tissue calcification andcardiovascular disease. Cardiovascular disease is the cause of death inalmost half of all dialysis patients.

Aluminum, calcium, and, more recently, lanthanum salts have beenprescribed to control phosphate ion absorption in the gastrointestinal(GI) tract and restore systemic phosphate levels back to normal. Howeverthese salts liberate soluble aluminum and calcium cations in the GItract, which are then partially absorbed into the blood stream. Aluminumabsorption can cause serious side effects such as aluminum bone diseaseand dementia; high calcium uptake leads to hypercalcemia and putspatients at risk for coronary calcification.

Metal-free phosphate binders such as strong base ion-exchangermaterials, Dowex and Cholestyramine resins, have been suggested for useas phosphate binders. However, their low capacity of binding requireshigh dosage that is not well tolerated by patients.

Amine functional polymers have been described as phosphate or oxalatebinders. For example, see U.S. Pat. Nos. 5,985,938; 5,980,881;6,180,094; 6,423,754; and PCT publication WO 95/05184. Renagel, acrosslinked polyallylamine resin, is a phosphate sequestering materialintroduced in the market as a metal-free phosphate binder. In vitrophosphate binding of Renagel is approximately 6 mmol/gm in water and 2.5mmol/gm when measured in 100 mM sodium chloride solution. Therecommended dosage for the targeted patient population is typicallybetween 5 gms/day to 15 gms/day to keep the phosphate concentrationbelow 6 mg/dL. Published phase I clinical trials on Renagel, performedon healthy volunteers, indicate that 15 gms of Renagel decrease thephosphate urinary excretion from a baseline of 25 mmole to 17 mmole, thedifference being excreted in the feces as free and polymer-boundphosphate. From these data, the in vivo capacity range can beestablished at 0.5-1 mmol/gm, which is much less than the in vitrocapacity of 2.5 mmol/gr measured in saline. Considering only the invitro binding capacity of Renagel measured in saline, a dosage of 15 gmof the 2.5 mmol/gm phosphate binder would bind the entire phosphorouscontent of the average American diet, i.e. 37 mmol/day. The discrepancybetween the in vitro binding capacity and the documented low in vivobinding capacity has a negative impact on the therapeutic benefit of thedrug since more resin is needed to bring the serum phosphate to a saferange.

This loss of capacity of ion-exchange resins is not limited to Renagelwhen used in the complex environment of the GI tract environment. Forexample, cation exchange resins in the sodium or ammonium form have beenadministered to patients with hyperkalemia. The exchange capacity ofthese resins were measured from isolated feces and found to be about 20%of the in vitro capacity (Agarwal, R., Gastroenterology, 1994, 107,548-571).

Although generally safe from a toxicological perspective, the large doseand inconvenience associated with taking multigram amounts of resin(e.g., up to 15 gms/day for Renagel and considerably higher in the casesof sodium-binding resins) argues for the need to improve resin capacity.As an example, even in reported safety studies of the Renagel binder,patients have noted gastrointestinal discomfort at doses as low as1.2-2.0 gm/day for an 8 week treatment period. Patients receiving 5.4 gmof Renagel/day were discontinued from treatment due to adverse eventssuch as GI discomfort in 8.9% of the cases (Slatapolsky, et al KidneyInt. 55:299-307, 1999; Chertow, et al Nephrol Dial Transplant14:2907-2914, 1999). Thus, an improvement in in vivo binding capacitythat translates to lower, better tolerated dosing would be a welcomeimprovement in resin-based therapies.

As a result of these considerations there is still a great need forsafe, high-capacity binders that selectively remove ions from the bodywith a lower drug dosage and a better patient compliance profile.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides core-shell compositionsand pharmaceutical compositions thereof. The core-shell compositions ofthe present invention comprise of a core component and a shellcomponent. In a preferred embodiment, the core of the core-shellcomposition is a polymer and can preferentially bind one or more targetsolutes, e.g., in the gastrointestinal (GI) tract of an animal. Inanother preferred embodiment, the permeability of the shell component ismodified based on the external environment.

Another aspect of the invention provides methods for treatment ofpatients using the core-shell compositions described herein. In apreferred embodiment, the core-shell compositions are used to removetarget solutes from the GI tract. Examples of target solutes that can beremoved from the GI tract include, but are not limited to, phosphate,oxalate, sodium, chloride, protons, potassium, iron, calcium, ammonium,magnesium, urea, and creatinine. In another preferred embodiment, thecompositions described herein are used in the treatment ofhyperphosphatemia, hypocalcemia, hyperparathyroidism, depressed renalsynthesis of calcitriol, tetany due to hypocalcemia, renalinsufficiency, ecotopic calcification in soft tissues, hypertension,chronic heart failure, end stage renal disease, liver cirrhosis, fluidoverload, sodium overload, hyperkalemia, metabolic acidosis, renalinsufficiency, and anabolic metabolism.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic representation of one embodiment of a core-shellcomposition.

FIG. 2 depicts the solute binding profile as a function of time for someembodiments of the invention.

FIG. 3 depicts the membrane preparation for determination of ionpermeability.

FIG. 4 depicts the binding data of different polyethyleneimine coatedbeads for different cations.

FIG. 5 depicts the effect of a Eudragit RL 100 shell on magnesium andpotassium binding.

FIG. 6 depicts binding of magnesium on benzylated polyethyleneiminecoated Dowex (K) beads.

FIG. 7 depicts the stability of Ben(84)-PEI coated Dowex (K) beads underacid conditions representative of the acidic conditions in the stomach.

FIG. 8 depicts potassium and magnesium binding by Dowex beads coatedwith benzylated polyethyleneimine.

FIG. 9 depicts magnesium binding by fluoroacrylic acid beads withbenzylated polyethylene imine shell.

FIG. 10 depicts a setup for determining membrane permeability.

FIG. 11 depicts the permeability of benzylated polyethyleneiminemembrane.

FIG. 12 depicts the permeability and permselectivity of membranescomprising of mixtures of Eudragit RL100 and Eudragit RS 100.

FIG. 13 depicts the effects of bile acids on potassium binding byDowex(Li) coated with polyethyleneimine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides core-shell polymeric compositions. Also,methods and kits for using these compositions are described herein.

Core Shell Composition

One aspect of the invention is a core-shell composition comprising acore component and a shell component. In a preferred embodiment, thecore-shell composition is a polymeric composition and the core componentcan preferentially bind one or more target solutes, e.g., in thegastrointestinal (GI) tract of an animal. The term “animal” and “animalsubject” as used herein includes humans as well as other mammals.

As shown in FIG. 1, in one embodiment, the core-shell compositioncomprises core-shell particles with a core component 2 and a shellcomponent 4. The core component is capable of preferentially binding oneor more target solutes and the shell component has a higher permeabilityfor the target solutes compared to the permeability for one or morecompeting solutes. The size of the arrows in FIG. 1 corresponds to themagnitude of the permeability of the solutes. In preferred embodiments,the shell of the core-shell composition is essentially not disintegratedduring the period of residence and passage through the gastro-intestinaltract.

The term “target solute” as used herein means a solute that ispreferentially bound and/or retained by the core component of thecore-shell composition. It is preferred that the target solute has ahigher permeability across the shell compared to one or more competingsolutes. In preferred embodiments, the shell preferentially allowscontact of the target solute with the core. Target solutes include bothions and non-ionic molecules. The ions include both organic andinorganic ions. The ions also include hydrophilic ions, hydrophobicions, hydrophilic neutral molecules, and hydrophobic neutral molecules.Examples of anionic target solutes include phosphate, chloride,bicarbonate, and oxalate ions. Examples of cationic target solutesinclude protons, sodium, potassium, magnesium, calcium, ammonium, andother heavy metal ions. Target solutes also include toxins such asuremic toxins. Examples of uremic toxins include urea, creatinine, andclasses of compounds such as ribonucleosides, guanidines, polyols,peptides, purines, pyrimidines. See Vanholder et al., KidneyInternational, vol. 63, (2003), 1934-1943.

In one embodiment, the target solutes excludes high molecular weightmolecules like proteins, polysaccharides, and cell debris whosemolecular weight are greater than about 50,000 daltons, preferablygreater than 5000 daltons. Target solutes also include non-ionicmolecules such as organic and inorganic neutral molecules, as well ashydrophilic and hydrophobic neutral molecules. For example, thenon-ionic molecules include biological toxins, enzymes, metabolites,drugs, bodily secretions, hormones, etc. Typically, the toxins bound bythe compositions disclosed herein are less than about 10,000 daltons,preferably less than 5000 daltons, and even more preferably less than2000 daltons. The compositions disclosed herein with suitable propertiescould be used to treat toxicities caused by uremia, drug overdoses orexposure to toxins such as biological toxins or chemical contaminants.

In one embodiment, the core-shell particle preferably binds targetsolutes, excluding bile acids. In another embodiment, the core-shellparticle preferably binds a bile acid and one additional target solutewhich is not a bile acid.

The term “competing solute” as used herein means solutes that competewith the target solute for binding to a core component, but that are notdesired to be contacted and/or bound to the core component. Typically,the competing solute for a core-shell composition depends on the bindingcharacteristics of the core and/or the permeability characteristics ofthe shell component. A competing solute can be prevented from contactingand/or binding to a core-shell particle due to the preferential bindingcharacteristics of the core component and/or the decreased permeabilityof the shell component for the competing solute from the externalenvironment. Typically, the competing solute has a lower permeabilityfrom the external environment across the shell compared to that of thetarget solute. For example, for a core-shell composition with a corecomponent that preferably binds phosphate ions, an example of acompeting solute is bile acids and fatty acids. The bile acids and fattyacids can be kept away from the core and not be allowed to bind to thecore due to the permeability barrier created by the shell component thatis more permeable to phosphate ions than bile acids.

In one embodiment, the target solute is hydrophilic ions. The core-shellpolymeric compositions which have hydrophilic ions as target solutes arepreferably used to remove hydrophilic ions from physiological fluids.More preferably, such core-shell compositions have utility inselectively removing phosphate, oxalate and/or chloride anions. Inanother embodiment, the hydrophilic ions removed are sodium and/orpotassium ions.

It is preferred that the core component of the core-shell particlespreferentially binds at least one target solute. The term “preferentialbinding” and its grammatical equivalents are used herein to describe thefavored binding of the target solute to the core component and/orcore-shell particles compared to the binding of competing solutes. Thepreferential binding of target solute can be due to a higher bindingaffinity for target solutes compared to competing solutes. Preferentialbinding also encompasses an increased amount of binding of targetsolutes by the core component, compared to the binding of competingsolutes. In some of the preferred embodiments, the core-shell particlesbind a greater amount of target solute compared to the core by itself inthe absence of the shell. The increased amount of binding can be fromabout 5% to 100%. It is preferred that the increase in binding of targetsolute in the presence of the shell compared to the amount bound in theabsence of the shell is about 10% or greater, more preferred is about25% or greater, even more preferred is about 50% or greater, and mostpreferred is about 95% or greater.

It is also preferred that the core-shell particles retain a significantamount of the bound target solute. The term “significant amount” as usedherein is not intended to mean that the entire amount of the boundtarget solute is retained. It is preferred that at least some of thebound solute is retained, such that a therapeutic and/or prophylacticbenefit is obtained. Preferred amounts of bound target solutes that areretained range from about 5% to about 100%. It is preferred that thecore-shell compositions retain about 50% of the bound target solute,more preferred is about 75%, and even more preferred is greater than95%. The period of retention of the bound sodium is preferred to beduring the time that the core-shell composition is being usedtherapeutically and/or prophylactically. In the embodiment in which thecore-shell composition is used to bind and remove target solutes fromthe gastro-intestinal tract, the retention period is preferred to beduring the time of residence of the composition in the gastro-intestinaltract. For a topical preparation or a core-shell composition used for alocal effect, the retention time is typically the period the compositionis present on the topical location or the location that the local effectis desired.

In one embodiment, the core component is composed of polymers containingfunctional groups with specific binding properties for a given solute,i.e. the target solute. The functional groups with the desired bindingproperties can be incorporated in the polymer backbone or pendant to thebackbone. The binding interactions between the target solutes and thefunctional groups of the binding core can be of various kinds including,but not limited to, acid-base, coulombic, dipolar, hydrogen bonding,covalent binding, P_(i) interaction, and combinations thereof.

In different embodiments of the invention, the preferential bindingbetween the target solute and the competing solutes can be controlled bythe rate of sorption of solutes within the core material or by the rateof permeation of the solutes across the shell component. That is, it ispossible to modify the affinity of a target solute for the corecomponent by modifying the overall permeation rate across the particlewhile keeping the binding core characteristics constant. Also, it ispossible to reverse the selectivity for a set of solutes for a givenbinding core, by creating a permeability coefficient difference in theshell.

Some of the characteristics of the shell membrane and the solutes thatinfluence the permeation of solutes across the core-shell particles are:

-   -   size and shape of the hydrated solute;    -   degree of association/aggregation of the solute (e.g., when        micelles are formed);    -   charge of the solutes;    -   hydration ratio of the shell;    -   mesh size of the shell; and    -   interaction between shell and solutes.

Other parameters also influence the overall mass transfer of solutes tothe interior of the core-shell particles:

-   -   specific surface area (i.e. particle diameter);    -   thickness of the shell; and    -   convection current at the outside of the particles.

When there are no chemical interactions between the polymericcomposition and the solute, the diffusion can be described by Fick'sfirst law:J _(s) =P/l(C _(o)-C _(i))

-   -   where J_(s) is the solute flux in g/cm²/s;    -   L is the membrane thickness (cm);    -   P is the permeability coefficient in cm²/s; and    -   C_(o)-C_(i) is the concentration gradient across the membrane.        The permeability coefficient is expressed as:        P=KD    -   where K is a dimension-less parameter (assimilated to the solute        partition coefficient between the membrane and the solution) and    -   D is the solute coefficient in the aqueous solution.        Several models are known to express the permeability coefficient        P, such as the capillary pore model (Renkin equation) and the        free volume model, among others.

In the free volume model, the polymeric composition that makes up thecore and/or shell component is considered to be a homogenously hydratednetwork. The diffusion transport of solutes is considered to occurthrough fluctuating water-filled spaces within the polymeric network.The free volume diffusion model predicts that D scales with the fractionof polymer in the membrane, φ, and the radius of the hydrated solute,r_(s). A refinement has been proposed (Peppas et al., J. Appl. Polym.Sci., 36,735-747, 1988) as the hydrodynamic model:

$\frac{D}{D_{0}} = {k_{1}{\exp\left\lbrack {{- k^{\prime}}{r_{s}^{2}\left( \frac{\phi}{1 - \phi} \right)}} \right\rbrack}\mspace{31mu}{diffusion}\mspace{14mu}{model}}$$\frac{D}{D_{0}} = {{\exp\left\lbrack {{- k_{c}}r_{s}\phi^{3/4}} \right\rbrack}\mspace{31mu}{hydrodynamic}\mspace{14mu}{model}}$

-   -   where D and D₀ are the diffusion coefficients in the membrane        and the aqueous solution, respectively and    -   k₁ is related to the sieving factor, when the geometry of the        solute is the critical parameter that dictates the solute        progression in the core-shell composition and k′ and k_(c) are        undefined structural factors.

For a target solute such as phosphate ions, a typical value ofself-diffusion coefficient is 10⁻⁵ cm²/s. Based on certain diffusionmodels, the permeation rate across a micron thick shell membrane isestimated to be extremely fast with respect to the time of use of theresin, typically hours.

If bile acid or fatty acid molecules, as the competing solutes, competefor the same core binding sites as phosphate ions, their self-diffusioncoefficient is, inversely proportional to their size in solution, whichis not so different from one of small ions. Thus, this self-diffusioncoefficient may not be enough to create a permeability barrier, if thediffusion is unhindered. Accordingly, in some embodiments, severalcharacteristics of the shell component are tuned so that a permeationdifference is established. For example, when the mesh size of the shellmaterial is in the same size range as the solute dimensions, the randomwalk of the bulkier solute through the shell component is significantlyslowed down. For example, experimental studies (Krajewska, B., Reactiveand Functional polymers 47, 2001, 37-47) report permeation coefficientsin cellulose ester or crosslinked chitosan gel membranes for both ionicand non-ionic solutes shows slowing down of bulkier solutes when meshsize nears solute dimensions. Accordingly, D values can decrease severalorders of magnitude depending on the molecular size of the solutes andthe polymer volume fraction in the core-shell compositions, the polymervolume fraction in the swollen resin being a good indicator of the meshsize within the composition. Theoretical studies have shown, forexample, that mesh size usually scales with φ^(−3/4), φ being thepolymer volume fraction in the shell component when swollen in asolution.

In some embodiments, the permeability of the solute is modulated by thedegree of interaction between the solute and the shell material. Astrong interaction can trap the solute inside the shell component,almost shutting down the migration across the shell. Examples of typesof interaction include ionic, covalent, polar, hydrogen bonding, van derWaals, and hydrophobic interactions.

In some embodiments, depending upon the conditions of use and the typeof solutes, the ratio between the diffusion coefficient of the targetsolute and the competing solutes through the shell, is between about1.1:1 to about 10⁹:1, preferably between about 2:1 to about 10⁶:1.

When the core-shell particles of the invention are used, the solutebinding profile as a function of time, of some embodiments, can beschematically represented as depicted in FIG. 2. In a preferredembodiment, the target solute migrates quickly through the shell to bebound to the core material quickly attaining its binding valuecorresponding to a non-competing mode. In contrast, the competing soluteslowly progresses through the shell as a result of its lower permeationrate; it eventually reaches its binding equilibrium value later in timeand then displaces the target solute, causing a drop in the targetsolute binding curve. Preferably the ratio of diffusion coefficients isadjusted so that, at the end of the time of use of the binder (which maycorrespond to mean residence time of the resin in the GI) is less thanabout 10% to about 100% of the competing solutes have reached theirbinding equilibrium value. Preferably less than about 10%, morepreferably less than about 50%, and even more preferably less than about75% of the competing solutes have reached their binding equilibriumvalue. For the target solutes more than about 10% to about 100% hasreached its binding equilibrium value in a non-competing mode.Preferably more than about 25%, more preferably more than about 50%,even more preferably more than about 75% of the target solute hasreached its binding equilibrium.

Methods for determining diffusion coefficients are known. For example,see, W. Jost, Diffusion in Solids, Liquids and Gases, Acad. Press,New-York, 1960). For example, the diffusion coefficient of a shellpolymer can be measured by casting it as a membrane over a solid porousmaterial, which is then contacted with a physiological solutioncontaining the solutes of interest, and measuring steady statepermeation rates of said solutes. Membrane characteristics can then beoptimized to achieve the best cooperation in terms of selectivity andpermeation rate kinetics. Structural characteristics of the membrane canbe varied by modifying, for example, the polymer volume fraction (in theswollen membrane), the chemical nature of the polymer(s), the polymerblend composition (if more than one polymer is used), the formulationwith additives such as wetting agents, plasticizers, and themanufacturing process.

Alternatively, if the shell membrane is applied to the core material ina separate coating process, then the selectivity effect provided by theshell can be obtained by measuring the binding capacity for the targetsolute using the core particles with and without the shell. The increasein selectivity, SI, can be simply expressed as the ratio of those twovalues, i.e. SI=CB_(core-shell)/CB_(core), where CB represent thecapacity of binding (i.e mole of solute per unit weight of particle).Preferably, SI is between about 1.05 to about 10⁴, even more preferablyfrom about 1.1 to about 10².

In some embodiments, the shell is a film-forming polymer. In anotherembodiment, the shell polymer forms a crosslinked gel With athree-dimensional network structure where chains are crosslinked throughcovalent bonds, ionic or other bonds. In yet another embodiment, theshell material is chemically identical to the binding core material, butthe crosslink density increases outward from core to shell. In anotherembodiment, the shell material adopts a “brush” configuration, whereinindividual polymer strands are covalently attached to the core materialat their termini. In this embodiment, the mesh size can be dictated bythe density of chains anchored onto the surface and by the chainmolecular weight. The polymer brush design variables that control thepermeability of polymer brushes to solutes of various sizes and/orweights are known in the art. For example, see WO 0102452 (andreferences therein).

Permeability is also controlled by the interaction of the solute withthe shell. A strong and, preferably, irreversible interaction of theshell with the competing solutes can trap the competing solutes withinthe encapsulating shell, slowing down their progression inward. Onemeans of quantifying the degree of interaction between a solute and theshell is the free energy of mixing, particularly the free enthalpy ofmixing, which can be predicted by solubility parameters. Solubilityparameters provide a numerical method of predicting the extent ofinteraction between materials, particularly liquids and polymers. Thismodel predicts that compounds with dissimilar solubility parameters willnot co-dissolve and consequently can go through the membrane unhinderedin the absence of size sieving effect. Conversely, compounds withsimilar solubility parameters may form a molecular solution and can beretained. Further, while solubility parameters poorly describe ionicinteractions, charged solutes generally are retained by shell materialof opposite charge. Also, the combination of hydrophobic and ionicinteractions can be used to provide strong, often irreversible,interactions with competing solutes, resulting in higher sorptionselectivity for the target solutes which display neither a hydrophobicor an ionic character.

The shell material can be chosen from natural or synthetic polymers,optionally crosslinked, alone or in combination with small moleculesfunctional additives such as wetting agents, plasticizers, permeabilityenhancers, solvents, moisturizing agents, pigment, and/or dyes.

Naturally-occuring or semi-synthetic polymers include: cellulose ethers(ethyl cellulose, methyl cellulose and their copolymers), celluloseesters (cellulose acetate, cellulose propionate, cellulose phthalate,and their copolymers), hydroxypropyl cellulose, hydroxyl ethylcellulose, chitosan, deacetylated chitosan, and the like. Other examplesof possible shell materials are listed in the table below:

TABLE 1 Acrylics Gums, vegetable Polyvinyl acetate Aquacoat ® aqueousdispersions Halocarbon Polyvinyl pyrrolidone Aquateric ® entericcoatings Hydrocarbon resins Polyvinyl alcohol Cellulose Acetate HydroxyPropyl Cellulose Polyvinyl chloride Cellulose Acetate Butyrate HydroxyPropyl Methyl Polyvinylacetate phthalate Cellulose Cellullose AcetatePhthalate Hydroxy Propyl Methyl Polyvinylidene chloride CellulosePhthalate Caseinates Kynar ® fluoroplastics Proteins Chlorinated rubberMaltodextrins Rubber, synthetic Coateric ® coatings Methyl CelluloseShellac Coating butters Microcrystalline wax Silicone Daran ® latex Milksolids Starches Dextrins Molasses Stearines Ethyl Cellulose NylonSucrose Enterics Opadry ® coating systems Surfactants Eudragits ®polymethacrylates Paraffin wax Surelease ® coating systems EthyleneVinyl Acetate Phenolics Teflon ® fluorocarbons Fats Polylactides WaxesFatty Acids Polyamino acids Zein Gelatin Polyethylene GlyceridesPolyethylene glycol Gums, vegetable

Examples of suitable synthetic polymers that can be used in the shellcomponent include polymers produced by free radical polymerization ofethylenic monomers (acrylic and methacrylic, styrenic, dienic, vinylic),polycondensates (polyester, polyamides, polycarbonate, polysulfone),polyisocyanate, polyurea, epoxy resins, and the like.

Shell deposition over the core material can be carried out using coatingtechniques such as spraying, pan coating, fluidized bed (Wurster coatingunits), dipping, solvent coacervation, polyelectrolyte inter-complexlayers, and the “layer by layer” encapsulation process. Otherencapsulation processes are also applicable. For example, seeEncapsulation and Controlled Release by R. A. Stephenson (Editor), DavidR. Karsa (Editor), 1993.

The shell can comprise several layers of distinct composition, of whichone can be an enteric coating (e.g. Eudragit acrylic polymers) thatdisintegrates and/or solubilizes at a specific location of the GI tract.Examples of suitable enteric coatings are known in the art, for examplesee Remington: The Science and Practice of Pharmacy by A. R. Gennaro(Editor), 20^(th) Edition, 2000.

The shell can also be grown on the core component through chemicalmeans, for example by:

-   -   chemical grafting of shell polymer to the core using living        polymerization from active sites anchored onto the core polymer;    -   interfacial reaction, i.e., a chemical reaction located at the        core particle surface, such as interfacial polycondensation; and    -   using block copolymers as suspending agents during the core        particle synthesis.

The interfacial reaction and use of block polymers are preferredtechniques when chemical methods are used. In the interfacial reactionpathway, typically, the periphery of the core particle is chemicallymodified by reacting small molecules or macromolecules on the coreinterface. For example, an amine containing ion-binding core particle isreacted with a polymer containing amine reactive groups such as epoxy,isocyanate, activated esters, halide groups to form a crosslinked shellaround the core.

In another embodiment, the shell is first prepared using interfacialpolycondensation or solvent coacervation to produce capsules. Theinterior of the capsule is then filled up with core-forming precursorsto build the core within the shell capsule.

Solvent coacervation is described in the art. For example, see Leach, K.et al., J. Microencapsulation, 1999, 16(2), 153-167. In this process,typically two polymers, core polymer and shell polymer are dissolved ina solvent which is further emulsified as droplets in an aqueous phase.The droplet interior is typically a homogeneous binary polymer solution.The solvent is then slowly driven off by careful distillation. Thepolymer solution in each droplet undergoes a phase separation as thevolume fraction of polymer increases. One of the polymer migrates to thewater/droplet interface and forms a more-or less perfect core-shellparticle (or double-walled microsphere).

Solvent coacervation is one of the preferred methods to deposit acontrolled film of shell polymer onto the core. In one embodiment, thecoacervation technique consists in dispersing the core beads in acontinuous liquid phase containing the shell material in a soluble form.The coacervation process then consists of gradually changing thesolvency of the continuous phase so that the shell material becomesincreasingly insoluble. At the onset of precipitation some of the shellmaterial ends up as a fine precipitate or film at the bead surface. Thechange in solvency can be triggered by a variety of physical chemistrymeans such as, but not limited to, changes in pH, ionic strength (i.e.osmolality), solvent composition (through addition of solvent ordistillation), temperature (e.g when a shell polymer with a LCST (lowercritical solution temperature) is used), pressure ( particularly whensupercritical fluids are used). More preferred are solvent coacervationprocesses when the trigger is either pH or solvent composition.Typically when a pH trigger event is used and when the polymer isselected from an amine type material, the shell polymer is firstsolubilized at low pH. In a second step the pH is gradually increased toreach the insolubility limit and induce shell deposition; the pH changeis often produced by adding a base under strong agitation. Anotheralternative is to generate a base by thermal hydrolysis of a precursor(e.g. thermal treatment of urea to generate ammonia). The most preferredcoacervation process is when a ternary system is used comprising theshell material and a solvent/non-solvent mixture of the shell material.The core beads are dispersed in that homogeneous solution and thesolvent is gradually driven off by distillation. The extent of shellcoating can be controlled by on-line or off-line monitoring of the shellpolymer concentration in the continuous phase. In the most common casewhere some shell material precipitates out of the core surface either ina colloidal form or as discrete particle, the core-shell particles areconveniently isolated by simple filtration and sieving. The shellthickness is typically controlled by the initial core to shell weightratio as well as the extent of shell polymer coacervation describedearlier. The core-shell beads can then be annealed to improve theintegrity of the outer membrane as measured by competitive binding.

In some embodiments, using the block copolymer approach, an amphiphilicblock copolymer can be used as a suspending agent to form the coreparticle in an inverse or direct suspension particle forming process.When an inverse water-in-oil suspension process is used, then the blockcopolymer comprises a first block soluble in the continuous oil phaseand another hydrophilic block contains functional groups that can reactwith the core polymer. When added to the aqueous phase, along withcore-forming precursor, and the oil phase, the block copolymer locatesto the water-in-oil interface and acts as a suspending agent. Thehydrophilic block reacts with the core material, or co-reacts with thecore-forming precursors. After the particles are isolated from the oilphase, the block copolymers form a thin shell covalently attached to thecore surface. The chemical nature and length of the blocks can be variedto vary the permeation characteristics of the shell towards solutes ofinterest.

In systems which combine positive charges and hydrophobicity, preferredshell polymers include amine functional polymers, such as thosedisclosed above, which are optionally alkylated with hydrophobic agents.

Alkylation involves reaction between the nitrogen atoms of the polymerand the alkylating agent (usually an alkyl, alkylaryl group carrying anamine-reactive electrophile). In addition, the nitrogen atoms which doreact with the alkylating agent(s) resist multiple alkylation to formquaternary ammonium ions such that less than 10 mol % of the nitrogenatoms form quaternary ammonium ions at the conclusion of alkylation.

Preferred alkylating agents are electrophiles such as compounds bearingfunctional groups such as halides, epoxides, esters, anhydrides,isocyanate, or αβ-unsaturated carbonyls. They have the formula RX whereR is a C1-C20 alkyl (preferably C4-C20), C1-C20 hydroxy-alkyl(preferably C4-C20 hydroxyalkyl), C6-C20 aralkyl, C1-C20 alkylammonium(preferably C4-C20 alkyl ammonium), or C1-C20 alkylamido (preferablyC4-C20 alkyl amido) group and X includes one or more electrophilicgroups. By “electrophilic group” it is meant a group which is displacedor reacted by a nitrogen atom in the polymer during the alkylationreaction. Examples of preferred electrophilic groups, X, include halide,epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups,the alkylation reaction causes opening of the three-membered epoxy ring.

Examples of preferred alkylating agents include a C3-C20 alkyl halide(e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decylhalide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, andcombinations thereof); a C1-C20 hydroxyalkyl halide (e.g., an11-halo-1-undecanol); a C1-C20 aralkyl halide (e.g., a benzyl halide); aC1-C20 alkyl halide ammonium salt (e.g., a (4-halobutyl)trimethylammonium salt, (6-halohexyl)trimethyl-ammonium salt,(8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammoniumsalt, (12-halododecyl)-trimethylammonium salts and combinationsthereof); a C1-C20 alkyl epoxy ammoniumn salt (e.g., a(glycidylpropyl)-trimethylammonium salt); and a C1-C20 epoxy alkylamide(e.g., an N-(2,3-eoxypropane)butyramnide,N-(2,3-epoxypropane)hexanamide, and combinations thereof). Benzylehalide and dodecyl halide are more preferred.

The alkylation step on the polyamine shell precursor can be carried outin a separate reaction, prior to the application of the shell onto thecore beads. Alternatively the alkylation can be done once the polyamineshell precursor is deposited onto the core beads. In the latter case,the alkylation is preferably performed with an alkylating agent thatincludes at least two electrophilic groups X so that the alkylation alsoinduces crosslinking within the shell layer. Preferred polyfunctionalalkylation agents include di-halo alkane, dihalo polyethylene glycol,and epichlorohydrine. Other crosslinkers containing acyl chlorides,isocyanate, thiocyanate, chlorosulfonyl, activated esters(N-hydroxysuccinimide), carbodiimide intermediates, are also suitable.

Typically, the level of alkylation is adjusted depending upon the natureof the polyamine precursor and the size of the alkyl groups used onalkylation. Some factors that play a role in the level of alkylationinclude:

-   -   (a) Insolubility of the shell polymer under conditions of the GI        tract. In particular, the low pH's prevailing in the stomach        tend to solubilize alkylated polyamine polymers whose pH of        ionization is 5 and above. For that purpose higher rate of        alkylation and higher chain length alkyl are preferred. As an        alternative, one may use an enteric coating to protect the shell        material against acidic pH's, said enteric coating is released        when the core-shell beads are progressing in the lower        intestine.    -   (b) The permselectivity profile: When the alkylation ratio is        low the persistence of the permselectivity for competing ions        (e.g. Mg²⁺, Ca²⁺) can be shorter than the typical residence time        in the colon. Conversely when the alkylation ratio (or the        weight fraction of hydrophobes) is high then the material        becomes almost impermeable to most inorganic cations, and thus,        the rate of equilibration for K⁺ becomes long.        Preferably, the degree of alkylation is selected by an iterative        approach monitoring the two variables mentioned above.

In a preferred embodiment, the shell is formed with Eudragit, forexample Eudragit RL 100 or RS 100 or a combination thereof, or withpolyethyleneimine (PEI). These shells maybe applied by solventcoacervation technique. The PEI may be optionally benzylated and alsooptionally cross-linked. Examples of suitable cross-linkers include, butare not limited to,

In some embodiments, the shell thickness can be between about 0.002micron to about 50 micron, preferably about 0.005 micron to about 20microns. Preferably the shell thickness is more than about 1 micron,more preferred is more than about 10 micron, even more preferred is morethan about 20 micron, and most preferred is more than about 40 micron.Preferably the shell thickness is less than about 50 micron, morepreferred is less than about 40 micron, even more preferred is less thanabout 20 micron, and most preferred is less than about 10 micron.

In another embodiment, the shell to core weight ratio comprises betweenabout 0.01% to about 50%, preferably between about 0.2% to about 10%.The size of the core-shell particles typically range from about 200 nmto about 2 mm, preferably being about 500 μm. Preferably the size of thecore-shell particles are more than about 1 μm, more preferred is morethan about 100 μm, even more preferred is more than about 200 μm, andmost preferred is more than about 400 μm. Preferably the size of thecore-shell particles are less than about 500 μm, more preferred is lessthan about 400 μm, even more preferred is less than about 200 μm, andmost preferred is less than about 100 μm.

The binding selectivity of the core can be assessed by standard methods.One method consists of measuring the binding capacity of the targetsolute in a simple model solution with non interfering species, Cm, andin a simulant medium (Cs), and calculating a selectivity index asSI=Cs/Cm. The core-shell particles of the invention are expected to haveselectivity indexes SI significantly higher than those reported forknown prior-art sorbent resins.

In one embodiment, the permeability of the shell changes as a functionof time. In particular, the permeability of the shell may change overtime when used in vivo. For example, in certain applications it ispreferable to either diminish or conversely increase the permeability totarget solutes over time during residence in a GI tract. For example,the resin could bind a hydrophilic ionic solute at a certain location ofthe GI tract at a rate controlled by the solute concentration inequilibrium with the resin at that location. As the resin travels downthe GI tract, the local target solute concentration may vary as a resultof dilution or solute transport across the gut membrane. In thisembodiment, the shell material is engineered to respond to suchconcentration or other physiological changes in the GI, so that itspermeability is altered; more specifically, the permeability of theshell maybe decreasedduring its journey through the GI so thathydrophilic ions are no longer able to cross the shell membrane, duringthe later period of the core-shell composition's residence in the GItract. This embodiment also applies to more hydrophobic solutes such asbile acids. In the case of bile acid sequesterants, studies have shownthat the poor binding rate in vivo is caused by the release of bileacids past the ileum segment of the gut. At that point, bile acids arealmost quantitatively reabsorbed by the mucosa, so that the bindingequilibrium is shifted and the sequestering capacity is lowered. In thisembodiment, the shell component has a permeability trigger thatdecreases the permeability of the shell to bile acids, when thecore-shell resin passes the ileum so that the overall capacity isconserved.

One manner of achieving this loss of permeability to hydrophilic ionsinvolves decreasing or even eliminating the free volume of permeation ofthe shell membrane. The free volume of permeation of the membrane can bemodified by controlling the hydration rate of the shell. In this manner,it is possible to almost shut down the rate of permeation by inducing ashell collapse. While there are many ways to induce such a phase change,the preferred approach consists of rendering the membrane materialincreasingly hydrophobic so that the hydration rate decreases almost tozero. This can be accomplished through several ways depending upon thetype of triggering mechanism. For example the triggering mechanism canbe by pH change. The pH profile of the gastrointestinal tract presentsseveral domains which may change as a function of time, but show someinvariants indicated below (Fallinborg et al. Aliment. Pharm. Therap.(1989),3,605-613):

TABLE 2 GI tract segment Ph range Stomach 1-2 Duodenum—distal smallintestine 6-7 Ceacum—ascending colon   7-5.5 Transverse—descending colon5.5-6   Feces 6.5

Shell polymers exhibiting a chain collapse in any of these pH regionswould be prone to permeability changes. For instance, core-shellparticles suitable for binding a solute selectively in the stomach andkeeping it in the particle core while the particles are moving down thesmall and large intestine, would display high permeability to solutes atlow pH and very low permeability at neutral pH. This can be done byhaving a shell polymer with hydrophobic groups and groups that ionizesubject to pH change. For example, polymers built from hydrophobicmonomers (e.g. long chain alcohol (meth)arylates, Nalkyl(meth)acrylamide), and basic monomers that ionize at low pH and remainneutral beyond their pKa (e.g. vinyl-pyridine, dialkylaminoethyl(meth)acrylamide) can be used. The relationship between pH and shellswelling ratio, and hence permeability, can be controlled by the balanceof hydrophobic monomers and ionizable monomers. Examples of such systemsare reported in the literature. For example, see Batich et al,Macromolecules, 26, 4675-4680.

A further drop in permeability may be desirable when pH increases (e.g.from ileum to colon) to prevent bound electrolytes being released as theresin environment changes. This can be achieved where the shell materialswitches from a hydrated state to a collapsed, impermeable state as thepH gets slightly basic. In such embodiments, shell polymers typicallycontain a balanced amount of hydrophobic and acidic monomers. Suchsystems are extensively described in the literature. For example, seeKraft et al. Langmuir, 2003, 19, 910-915; Ito et al,Macromolecule,(1992), 25,7313-7316.

Another means of changing shell permeability is by passive absorption.As described above, components present in the GI tract, whether comingfrom the diet, produced as diet digest metabolites, from secretion, etc.are susceptible to adsorption on and within the shell in aquasi-irreversible manner and this adsorption may modify thepermeability pattern by inducing membrane collapse. The vast majority ofthese GI tract components is negatively charged and shows various levelsof hydrophobicity. Some of these species have an amphiphilic character,such as fatty acids, bile acids, phospholipids, and biliary salts andbehave as surfactants. Surfactants can adsorb non-specifically tosurfaces through hydrophobic interactions, ionic interaction andcombinations thereof. In the context of the present invention, thisphenomenon can be used to change the permeability of the resin upon thecourse of binding to these surfactants during the resin's residence inthe GI tract.

For example, fatty acids and bile acids both form insoluble complexeswhen mixed with positively charged polymers. For example, see Kaneko etal, Macromolecular Rapid Communications, 2003, 24(13), 789-792). Bothtypes of molecules present similarities with synthetic anionicsurfactants, and numerous studies report the formation of insolublecomplexes between anionic surfactants and cationically charged polymers.For example, see Chen, L. et al, Macromolecules (1998), 31(3), 787-794.In this embodiment, the shell material is selected from copolymerscontaining both hydrophobic and cationic groups, so that the shell formsa complex, preferably a tight complex, with anionically chargedhydrophobs typically found in the GI tract, such as bile acids, fattyacids, bilirubin and related compounds. Suitable compositions alsoinclude polymeric materials described as bile acids sequestering agents,such as those reported in U.S. Pat. No. 5,607,669, U.S. Pat. No.6,294,163, U.S. Pat. No. 5,374,422, Figuly et al, Macromolecules, 1997,30, 6174-6184. The formation of this complex induces a shell membranecollapse which in turn lowers or shuts down the permeation rate acrossthe said membrane.

The shell permeability may also be modulated by enzymatictransformation. In one embodiment the shell comprises a hydrophobicbackbone with pendant hydrophilic entities that are cleaved off via anenzymatic reaction in the gut. As the enzymatic reaction proceeds, thepolymer membrane becomes more and more hydrophobic, and turns from ahigh swollen, high permeability material to a fully collapsed lowhydration membrane with minimal permeability. Hydrophilic entities canbe chosen amongst natural substrates of enzymes commonly secreted in theGI tract. Such entities include amino acids, peptides, carbohydrates,esters, phosphate esters, oxyphosphate monoesters, O- andS-phosphorothioates, phosphoramidates, thiophosphate, azo groups andother similar entities. Examples of enteric enzymes which can be used tochemically alter the shell polymer include, but are not limited to,lipases, phospholipases, carboxylesterase, glycosidases, azoreductases,phosphatases, amidases and proteases.

In some embodiments, the core material is chosen from polymercompositions with the desired ion binding properties. Examples ofsuitable polymers material include, but are not limited to:

-   -   1) anion binding materials such as amine functional polymers        such as those described in U.S. Pat. Nos. 5,985,938; 5,980,881;        6,180,094; 6,423,754; and PCT publication WO 95/05184 and    -   2) cation exchange polymers, such as those with acid functional        groups such as carboxylate, phosphonate, sulfate, sulfonate,        sulfamate functional polymers and combinations thereof.

Core-shell compositions that include anion binding materials are usefulfor the binding and removal from GI tract of phosphate, chloride,bicarbonate, and oxalate ions. The cation exchange polymers have utilityin binding and removal of physiologically important cations such asprotons, sodium, potassium, magnesium, calcium, ammonium, and the likeor heavy metals which cause poisoning.

Examples of other suitable polymers for the core component are describedin the following co-pending patent applications: 1) Polyamine Polymers,filed on Nov. 3, 2003, application Ser. No.: 10/701,385 and 2)Crosslinked Amine Polymers, filed on Mar. 22, 2004, application Ser. No.10/806,495.

Further examples of compositions that can be used in the core componentinclude the phosphate binders in PCT publications WO 94/19379, WO96/25440, WO 01/28527, WO 02/85378, WO 96/39156, WO 98/42355, WO99/22743, WO 95/05184, WO 96/21454, and WO 98/17707; U.S. Pat. Nos.5,698,190; 5,851,518; 5,496,545; 5,667,775; 6,083,495; and 6,509,013;and European Patent Application 01200604.5.

Aluminum, calcium, and lanthanum salts are used as phosphate binders.Examples of inorganic metal salts used as phosphate binders includealuminum carbonate, aluminum hydroxide gel (Amphojel®), calciumcarbonate, calcium acetate (PhosLo), and lanthanum carbonate (Fosrenol).In one embodiment, the core-shell particle comprises of a core componentcomprising of a metal phosphate binder, such as aluminum carbonate,aluminum hydroxide gel, calcium carbonate, calcium acetate, andlanthanum carbonate.

In one embodiment, the core component has sodium ion binding properties.Suitable polymers that can be used in the core so as to impart the coresodium-binding properties include crown ethers. Crown ethers exhibitselectivity for certain alkali metals over others, based mainly on thehole-size of the crown ether size and the size of the metal. Crownethers of the type 15-18 are preferred for use in sodium ion bindingcore components. Also, other suitable compositions for sodium bindingproperties are described in co-pending patent application entitled“Methods and Compositions for Treatment of Ion Imbalances,” filed onMar. 30, 2004, application Ser. No. 10/814,527.

Uses of the Core-shell Compositions

In one aspect, the invention provides methods of preferentially bindingsolutes in a mammal, comprising the step of administering to the mammala therapeutically effective amount of core-shell compositions. Coreshell compositions that bind hydorphillic cations and/or anions can beused to control ion homeostasis and treat electrolyte balance disordersin phosphate (hyperphosphatemia), oxalate (calcium oxalate kidneystones, oxaluria), sodium (hypertension), potassium (hyperkalemia),chloride (acidosis), or to remove toxic metals or oxidative anions incases of poisoning.

The core-shell compositions with anion exchange resins are particularlyuseful in the binding and excretion of negatively charged ions from thebody. Core-shell compositions can also be used to bind metallic ions.These compositions can be administered orally to bind and remove from ananimal various negatively charged entities and metallic species from thegastro-intestinal tract. In one embodiment, the core-shell compositionsof the present invention are used to remove phosphate, oxalate, bileacids, small molecules, proteins, metallic ions such as those comprisedwithin the 6th and the 11th groups and 4th and 6th periods of thePeriodic Table, also including the Lanthanoids and the Actanoids.

In some embodiments, the core-shell compositions with polyvicinalamines,such as those described in co-pending U.S. patent application Ser. No.10/701,385; entitled Polyamine Polymers, filed on Nov. 3, 2003 areuseful in the treatment of renal diseases, hyperphosphatemia, and theremoval of bile acids, oxalates and iron from the gastrointestinaltract.

In some embodiments, the core-shell compositions are used in thetreatment of phosphate imbalance disorders. The term “phosphateimbalance disorder” as used herein refers to conditions in which thelevel of phosphorus present in the body is abnormal. One example of aphosphate imbalance disorder includes hyperphosphatemia. The term“hyperphosphatemia” as used herein refers to a condition in which theelement phosphorus is present in the body at an elevated level.Typically, a patient is often diagnosed with hyperphosphatemia if theblood phosphate level is, for example, above 4.5 milligrams perdeciliter of blood and/or glomerular filtration rate is reduced to, forexample, more than about 20%

Other diseases that can be treated with the methods and compositions ofthe present invention include hypocalcemia, hyperparathyroidism,depressed renal synthesis of calcitriol, tetany due to hypocalcemia,renal insufficiency, and ecotopic calcification in soft tissuesincluding calcifications in joints, lungs, kidney, conjuctiva, andmyocardial tissues. Also, the present invention can be used to treatESRD and dialysis patients. In one embodiment, the core-shellcompositions are used for prophylactic treatment of diseases.

The core-shell compositions described herein can also be used to treatdiseases wherein a reduction in physiological levels of salt is desired.The core-shell compositions, depending on the ion binding properties ofthe core component, can be used to remove cations such as sodium and/oranions such as chloride.

In one embodiment, the core-shell compositions of the present inventionare used to treat metallic poisoning, like iron poisoning. Ironpoisoning typically is a result of children inadvertently taking ironsupplement tablets. In iron overdose, binding of iron to oral charcoal,bicarbonate, deferoxamine, or magnesium hydroxide are typicaltreatments. Gastric lavage and profuse oral fluids are used to try toflush out the iron tablets. Non-absorbable core-shell compositions withiron chelating properties can be used for removal of metallic iron.

Depending on the properties of the core and/or shell components, thecore-shell compositions of the present invention also show utility inbinding dietary oxalate in patients who suffer from hyperoxaluria, i.e.abnormally high levels of oxalate in the urine. Elevated urine oxalatelevels are one of the causes of calcium-stone formation (i.e., kidneystones). Most calcium stones are composed of calcium oxalate, eitheralone or in combination with calcium phosphate or calcium urate.Elevated urinary oxalate levels can result from excessive dietary intakeof oxalate (dietary oxaluria), gastrointestinal disorders that lead tomalabsorption of oxalate (enteric oxaluria), or an inherited enzymedeficiency that results in excessive metabolism of oxalate (primaryhyperoxaluria or PH). Dietary and enteric oxaluria can be treated withdiet restriction or modifications to restrict intake of foods with highoxalate content. However patient compliance is often difficult owing tothe wide distribution of oxalate and purine derivatives in many foods.Calcium carbonate tablets (500-650 mg/tablet; 3 tablets per meal) canalso be taken to bind and remove intestinal oxalate, but again patientcompliance is difficult owing to the amount of calcium carbonate needed.Core components made of polyvicinalamines, such as those describedco-pending U.S. patent application Ser. No. 10/701,385; entitledPolyamine Polymers, filed on Nov. 3, 2003, have high binding constantsfor oxalate and can be used to remove oxalate from the gastro-intestinaltract and subsequently lower the risk of kidney stone formation.

In the present invention, the core-shell compositions can beco-administered with other active pharmaceutical agents depending on thecondition being treated. This co-administration can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.For example, for the treatment of hyperphosphatemia, the core-shellcompositions can be co-administered with calcium salts which are used totreat hypocalcemia resulting from hyperphosphatemia. The calcium saltand core-shell composition can be formulated together in the same dosageform and administered simultaneously. Alternatively, the calcium saltand core-shell composition can be simultaneously administered, whereinboth the agents are present in separate formulations. In anotheralternative, the calcium salt can be administered just followed by thecore-shell composition, or vice versa. In the separate administrationprotocol, the core-shell composition and calcium salt may beadministered a few minutes apart, or a few hours apart, or a few daysapart.

The term “treating” as used herein includes achieving a therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication, amelioration, or prevention of the underlying disorderbeing treated. For example, in a hyperphosphatemia patient, therapeuticbenefit includes eradication or amelioration of the underlyinghyperphosphatemia. Also, a therapeutic benefit is achieved, with theeradication, amelioration, or prevention of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of core-shell compositions to a patientsuffering from renal insufficiency and/or hyperphosphatemia providestherapeutic benefit not only when the patient's serum phosphate level isdecreased, but also when an improvement is observed in the patient withrespect to other disorders that accompany renal failure and/orhyperphosphatemia like ectopic calcification and renal osteodistrophy.For prophylactic benefit, the core-shell compositions may beadministered to a patient at risk of developing hyperphosphatemia or toa patient reporting one or more of the physiological symptoms ofhyperphosphatemia, even though a diagnosis of hyperphosphatemia may nothave been made.

The pharmaceutical compositions of the present invention includecompositions wherein the core-shell compositions are present in aneffective amount, i.e., in an amount effective to achieve therapeutic orprophylactic benefit. The actual amount effective for a particularapplication will depend on the patient (e.g., age, weight, etc.), thecondition being treated, and the route of administration. Determinationof an effective amount is well within the capabilities of those skilledin the art, especially in light of the disclosure herein.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievecirculating and/or gastrointestinal concentrations that have been foundto be effective in animals.

The dosages of the core-shell compositions in animals will depend on thedisease being, treated, the route of administration, the physicalcharacteristics of the patient being treated, and the composition of thecore and shell components. Dosage levels of the core-shell compositionsfor therapeutic and/or prophylactic uses can be from about about 0.5gm/day to about 30 gm/day. It is preferred that these polymers areadministered along with meals. The compositions may be administered onetime a day, two times a day, or three times a day. Most preferred doseis about 15 gm/day or less. A preferred dose range is about 5 gm/day toabout 20 gm/day, more preferred is about 5 gm/day to about 15 gm/day,even more preferred is about 10 gm/day to about 20 gm/day, and mostpreferred is about 10 gm/day to about 15 gm/day.

In some embodiments, the amount of target solute bound and/or retainedby the core-shell particles is greater than the amount if the corecomponent is used in the absence of the shell. Hence, the dosage of thecore component in some embodiments is lower when used in combinationwith a shell compared to when the core is used without the shell. Hence,in some embodiments of the core-shell pharmaceutical compositions, theamount of core component present in the core-shell pharmaceuticalcomposition is less than the amount that is administered to an animal inthe absence of the shell component.

Preferably, the core-shell compositions used for therapeutic and/orprophylactic benefits can be administered alone or in the form of apharmaceutical composition. The pharmaceutical compositions comprise ofthe core-shell compositions, one or more pharmaceutically acceptablecarriers, diluents or excipients, and optionally additional therapeuticagents. The compositions can be administered by injection, topically,orally, transdermally, or rectally. Preferably, the core-shellcomposition or the pharmaceutical composition comprising the core-shellcomposition is administered orally. The oral form in which thecore-shell composition is administered can include powder, tablet,capsule, solution, or emulsion. The therapeutically effective amount canbe administered in a single dose or in a series of doses separated byappropriate time intervals, such as hours.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Suitable techniquesfor preparing pharmaceutical compositions of the core-shell compositionsare well known in the art.

In addition to the uses of the core-shell compositions described hereinin the gastro-intestinal tract, these compositions can also be used forproducing local effects in other parts of the body, for example intopical formulations for local effects on the skin or in systemicformulations for producing local effects in particular organs, like theliver or the heart.

In some embodiments the polymers of the invention are provided aspharmaceutical compositions in the form of chewable tablets. In additionto the active ingredient, the following types of excipients are commonlyused: a sweetening agent to provide the necessary palatability, plus abinder where the former is inadequate in providing sufficient tablethardness; a lubricant to minimize frictional effects at the die wall andfacilitate tablet ejection; and, in some formulations a small amount ofa disintegrant is added to facilitate mastication. In general excipientlevels in currently-available chewable tablets are on the order of 3-5fold of active ingredient(s) whereas sweetening agents make up the bulkof the inactive ingredients.

The present invention provides chewable tablets that contain a polymeror polymers of the invention and one or more pharmaceutical excipientssuitable for formulation of a chewable tablet. The polymer used inchewable tablets of the invention preferably has a swelling ratio whiletransiting the oral cavity and in the esophagus of less than about 5,preferably less than about 4, more preferably less than about 3, morepreferably less than 2.5, and most preferably less than about 2. Thetablet comprising the polymer, combined with suitable excipients,provides acceptable organoleptic properties such as mouthfeel, taste,and tooth packing, and at the same time does not pose a risk to obstructthe esophagus after chewing and contact with saliva.

In some aspects of the invention, the polymer(s) provide mechanical andthermal properties that are usually performed by excipients, thusdecreasing the amount of such excipients required for the formulation.In some embodiments the active ingredient (e.g., polymer) constitutesover about 30%, more preferably over about 40%, even more preferablyover about 50%, and most preferably more than about 60% by weight of thechewable tablet, the remainder comprising suitable excipient(s). In someembodiments the polymer comprises about 0.6 gm to about 2.0 gm of thetotal weight of the tablet, preferably about 0.8 gm to about 1.6 gm. Insome embodiments the polymer comprises more than about 0.8 gm of thetablet, preferably more than about 1.2 gm of the tablet, and mostpreferably more than about 1.6 gm of the tablet. The polymer is producedto have appropriate strength/friability and particle size to provide thesame qualities for which excipients are often used, e.g., properhardness, good mouth feel, compressibility, and the like. Unswelledparticle size for polymers used in chewable tablets of the invention isless than about 80, 70, 60, 50, 40, 30, or 20 microns mean diameter. Inpreferred embodiments, the unswelled particle size is less than about80, more preferably less than about 60, and most preferably less thanabout 40 microns.

Pharmaceutical excipients useful in the chewable tablets of theinvention include a binder, such as microcrystalline cellulose,colloidal silica and combinations thereof (Prosolv 90), carbopol,providone and xanthan gum; a flavoring agent, such as sucrose, mannitol,xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such asmagnesium stearate, stearic acid, sodium stearyl fumurate and vegetablebased fatty acids; and, optionally, a disintegrant, such ascroscarmellose sodium, gellan gum, low-substituted hydroxypropyl etherof cellulose, sodium starch glycolate. Other additives may includeplasticizers, pigments, talc, and the like. Such additives and othersuitable ingredients are well-known in the art; see, e.g., Gennaro AR(ed), Remington's Pharmaceutical Sciences, 20th Edition.

In some embodiments the invention provides a pharmaceutical compositionformulated as a chewable tablet, comprising a polymer described hereinand a suitable excipient. In some embodiments the invention provides apharmaceutical composition formulated as a chewable tablet, comprising apolymer described herein, a filler, and a lubricant. In some embodimentsthe invention provides a pharmaceutical composition formulated as achewable tablet, comprising a polymer described herein, a filler, and alubricant, wherein the filler is chosen from the group consisting ofsucrose, mannitol, xylitol, maltodextrin, fructose, and sorbitol, andwherein the lubricant is a magnesium fatty acid salt, such as magnesiumstearate.

The tablet may be of any size and shape compatible with chewability andmouth disintegration, preferably of a cylindrical shape, with a diameterof about 10 mm to about 40 mm and a height of about 2 mm to about 10 mm,most preferably a diameter of about 22 mm and a height of about 6 mm.

In one embodiment, the polymer is pre-formulated with a high Tg/highmelting point low molecular weight excipient such as mannitol, sorbose,sucrose in order to form a solid solution wherein the polymer and theexcipient are intimately mixed. Method of mixing such as extrusion,spray-drying, chill drying, lyophilization, or wet granulation areuseful. Indication of the level of mixing is given by known physicalmethods such as differential scanning calorimetry or dynamic mechanicalanalysis.

Methods of making chewable tablets containing pharmaceuticalingredients, including polymers, are known in the art. See, e.g.,European Patent Application No. EP373852A2 and U.S. Pat. No. 6,475,510,and Remington's Pharmaceutical Sciences, which are hereby incorporatedby reference in their entirety.

In some embodiments the polymers of the invention are provided aspharmaceutical compositions in the form of liquid formulations. In someembodiments the pharmaceutical composition contains an ion-bindingpolymer dispersed in a suitable liquid excipient. Suitable liquidexcipients are known in the art; see, e.g., Remington's PharmaceuticalSciences.

EXAMPLES Example 1 Synthesis of Core-shell Crosslinked PolyallylamineParticles

In this process, spherical particles were formed by an inversesuspension procedure wherein a prepolymer (polyallylamine) iscrosslinked with epichlorohydrine. A block copolymer was used to impartmechanical stability to the droplets during the crosslinking reactionand provide a shell membrane chemically anchored to the core particle.

General Procedure for Block Copolymers Synthesis

The block copolymers were prepared by RAFT living free radicalpolymerization method, using a dithiocarbazide compound as a reversiblechain transfer agent (CTA) and a diazonitrile free radical initiator(AMVN) indicated below:

Synthesis of Poly(n-butyl acrylate-co-t-butyl acrylate) First Block

n-Butyl acrylate (25 g, 195 mmol) and t-butyl acrylate (25 g, 195 mmol)were combined with the CTA (173:1 Monomer:CTA, 616 mg, 2.26 mmol)) andAIBN (18.6 mg, 0.113 mmol). The monomer to CTA ratio is fixed so thatthe theoretical number average molecular weight (Mn) is 20,000 g.mol at90% conversion. The solution was stirred while purging with Ar for 20minutes at room temperature. After this time, it was heated to 65° C.under Ar while stirring for 3 hours and then cooled to room temperature.¹H NMR in CDCl₃ showed 87% conversion based on disappearance of monomer.The crude polymer was dissolved in 50 ml of acetone and precipitatedinto 900 ml of a 9:1(v/v) methanol: water solution. After several hours,the polymeric oil had separated to the bottom and the top layer wasdiscarded. The polymeric oil was dried in vacuum to yield 44 g (88%yield) of extremely thick yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=4.15-3.95 (2H, bm), 2.45-2.05 (2H, bm). 1.95-1.75 (1H, bm), 1.60-1.5(5H, bm), 1.5-1.3 (11H, bm), 0.93 (3H, t). GPC (THF, polystyrenestandards): Mn=25900; PDI=1.13. GPC (DMF, polyethyleneglycol standards):Mn=6600; PDI=1.58.

Following this procedure, 4 different first blocks were prepared, whichare listed in TABLE 3 as Example 1-1 to 1-4.

TABLE 3 Ex- Molecular am- weight ple Identification Composition (g/mol)1-1 nBA1tBA1_20k n-butyl acrylate-co-t-butyl 20,000 acrylate 50/50 mol-%1-2 nDiBA1tBA1_20k N,N-di-n-butyl acrylamide- 20,000 co-t-butyl acrylate50/50 mol-% 1-3 nBA1tBA1_50k n-butyl acrylate-co-t-butyl 50,000 acrylate50/50 mol-% 1-4 nDiBA1tBA1_50k N,N-di-n-butyl acrylamide- 50,000co-t-butyl acrylate 50/50 mol-%

Synthesis of Poly[(n-butyl acrylate-co-t-butylacrylate)-b-(N,N-dimethylacrylamide-co-glycidyl methacrylate)]

Theoretical Mn=20,000 1^(st) block and Mn=5000 2^(nd) block at 80% con.A solution of poly(n-butyl acrylate-co-t-butyl acrylate) terminated withthe CTA (2.53 ml, 40 wt % in DMF) and a solution of AMVN (48.1 μl,0.00736 mmol, 4 wt % in DMF) were combined manually. The mixture wasthen purged with Ar for 20 minutes. While stirring at room temperature,N,N-dimethylacrylamide (27.5 μl, 0.267 mmol) and a solution of glycidylmethacrylate (14.3 μl, 0.0296 mmol, 30 wt % in DMF) were added. Thesolution temperature was then raised to 55° C. over 30 minutes whilestirring. At this time, N,N-dimethylacrylamide (10.3 μl, 0.100 mmol) anda solution of glycidyl methacrylate (5.4 μl, 0.0111 mmol, 30 wt % inDMF) were added via a robot. Every 10 minutes for the next 4 hoursN,N-dimethylacrylamide (10.3 μl, 0.100 mmol) and a solution of glycidylmethacrylate (5.4 μl, 0.0111 mmol, 30 wt % in DMF) were added while thesolution stirred under Ar at 55° C. After all additions had beencompleted, the solution was stirred for an additional 2 hours under Arat 55° C. and then cooled to room temperature. The crude polymer wasdissolved in 2 ml acetone and precipitated into 30 ml water. Theresulting mixture was centrifuged at 1000 rpm for 60 minutes and theupper water layer then removed. The polymeric powder was washed with anadditional 10 ml of water, centrifuged, and the water layer removed. Theresulting wet powder was dried under vacuum at 30° C. to give a viscousliquid. Subsequent lyophilization provided 1.19 g (92% yield) of asticky solid. GPC (DMF, polyethyleneglycol standards): Mn=8500;PDI=2.10.

Similar procedures were used to make block copolymers of various lengthand chemical compositions which are reported in the following tables,TABLES 4 and 5.

TABLE 4 Library: Plate 1 (ID: 100436) Unit: mg Row Col nDiBA1tBA1 20knDiBA1tBA1 50k DMF THF AMVN GMA DMA A 1 1065.7 0.0 754.2 707.3 2.0 45.8287.3 A 2 915.9 0.0 709.1 665.0 1.7 78.7 493.8 A 3 714.9 0.0 648.6 608.21.3 122.8 770.8 A 4 1065.7 0.0 754.2 707.3 2.0 45.8 287.3 A 5 915.9 0.0709.1 665.0 1.7 78.7 493.8 A 6 714.9 0.0 648.6 608.2 1.3 122.8 770.8 B 1982.0 0.0 810.5 760.1 1.8 116.8 190.1 B 2 798.9 0.0 806.5 756.3 1.5190.1 309.2 B 3 581.8 0.0 801.7 751.8 1.1 276.8 450.4 B 4 982.0 0.0810.5 760.1 1.8 116.8 190.1 B 5 798.9 0.0 806.5 756.3 1.5 190.1 309.2 B6 581.8 0.0 801.7 751.8 1.1 276.8 450.4 C 1 0.0 897.8 622.9 584.1 0.738.6 242.0 C 2 0.0 770.4 585.8 549.3 0.6 66.2 415.3 C 3 0.0 600.1 536.1502.7 0.4 103.1 647.0 C 4 0.0 897.8 622.9 584.1 0.7 38.6 242.0 C 5 0.0770.4 585.8 549.3 0.6 66.2 415.3 C 6 0.0 600.1 536.1 502.7 0.4 103.1647.0 D 1 0.0 826.5 670.8 629.0 0.6 98.3 160.0 D 2 0.0 671.1 668.2 626.70.5 159.7 259.8 D 3 0.0 487.7 665.3 623.9 0.4 232.1 377.6 D 4 0.0 826.5670.8 629.0 0.6 98.3 160.0 D 5 0.0 671.1 668.2 626.7 0.5 159.7 259.8 D 60.0 487.7 665.3 623.9 0.4 232.1 377.6 General Design and Variations fromExample(mol:mol ratios) Starting Rows A, B = 20k 1:1 N,N-di-n-ButylBlock Acrylamide:t-Butyl Acylate (45.5 wt % Rows C, D = 50k 1:1N,N-di-n-Butyl solns): Acrylamide:t-Butyl Acylate Initiator: AMVNTemperature: 60 C. 2nd Block Compostion: Rows A, C = 1:9 GMA:DMA Rows B,D = 3:7 GMA:DMA Block Target Mn: A1, B1, A4, B4 = 5k A2, B2, A5, B5 =10k A3, B3, A6, B6 = 20k C1, D1, C4, D4 = 12.5k C2, D2, C5, D5 = 25k C3,D3, C6, D6 = 50k 2nd Block Method: Columns 1, 2, 3 = Batch AdditionColumns 4, 5, 6 = Spot Addition

TABLE 5 Library: Plate 1 (ID: 100369) Unit: mg Row Col GMA DMF nBA1tBA120k DMA AIBN A 1 39.8 1566.0 963.2 249.2 1.2 A 2 72.5 1458.0 842.7 454.21.0 A 3 116.8 1311.6 679.3 732.2 0.8 A 4 39.8 1566.0 963.2 249.2 1.2 A 572.5 1458.0 842.7 454.2 1.0 A 6 116.8 1311.6 679.3 732.2 0.8 B 1 74.21604.6 935.9 206.6 1.2 B 2 132.1 1532.2 800.2 368.0 1.0 B 3 206.6 1439.1625.7 575.5 0.8 B 4 74.2 1604.6 935.9 206.6 1.2 B 5 132.1 1532.2 800.2368.0 1.0 B 6 206.6 1439.1 625.7 575.5 0.8 General Design (mol:molratios) Starting Block: 20k 1:1 n-Butyl Acrylate:t-Butyl AcylateInitiator: AIBN Temperature: 65 C. 2nd Block Compostion: Row A = 1:9GMA:DMA Row B = 2:8 GMA:DMA 2nd Block Target Mn: Columns 1, 4 = 5kColumns 2, 5 = 10k Columns 3, 6 = 20k 2nd Block Method: Columns 1, 2, 3= Batch Addition Columns 4, 5, 6 = Spot Addition

General Procedure for the Synthesis of Core/shell CrosslinkedPolyallylamine Particles

Preparation of polyallylamine (PAA) solution: Polyallylaminehydrochloride (Mw 15,000) was dissolved in water, and NaOH was added toneutralize 25 mol % of hydrochloride. The concentration of polyallyaminehydrochloride in solution was 33 wt. %.

Preparation of diblock copolymer solution: diblock copolymer wasdissolved in toluene at 5 wt. %.

Preparation of core/shell particles: To 15 ml glass reactor was chargedPAA solution, diblock copolymer solution, and toluene, and some typicalsolution compositions as shown in Tables 4-9. The mixture was emulsifiedwith an Ultra-Turrax for 30 seconds and a magnetic stir bar was put intothe suspension. The suspension was stirred and heated at 60° C. for 30minutes and epichlorohydrin (10 mol % based on amine groups) was added.The suspension was further stirred at 60° C. for 8 hours and then cooledto room temperature.

Purification of core/shell particles: To the reaction mixture above,methanol (10 mL) was added and white particles precipitated out. Themixture was shaken for 30 minutes and centrifuged. The white particlesseparated from supernatant solution and collected. The white particleswere further washed with methanol (10 mL×2) and water (10 mL×3) byrepeating the same shake/centrifuge procedure. Finally the particleswere freeze-dried for three days.

Example 2 Synthesis of 1,3-Diaminopropane/epichlorohydrin CrosslinkedBeads (Referred to herein as: Bead-Pi-4-s)

The reaction vessel used was a 3-liter, three necked round bottom flaskwith four side baffles, equipped with an oil heating bath, cold-waterreflux condenser, and mechanical stirrer with a 3 inch propeller. Tothis reaction vessel is introduced a solution of 1,3-diaminopropane(90.2 g, 1.21 mole) dissolved in 90.2 g of water, surfactant (brancheddodecylbenzene sulfonic acid sodium salt, 6.4 g dissolved in 100 g ofwater), and 1 Kg of toluene. This initial charge is agitated to 600 rpmfor 2 minutes and then lowered to 300 rpm for 10 minutes before thefirst addition of epichlorohydrin. This speed is maintained through outthe experiment. The solution was heated to 80° C. and maintained at thistemperature throughout the experiment.

Into a separate vessel, a 40 mass % solution of epichlorohydrin intoluene was prepared. Using a syringe pump, 1.2 equivalents ofepichlorohydrin (134.7 g, (1.45 mole)) was added over a 3 hour period.The reaction was continued for an additional 2 hours before adding 0.75equivalents of sodium hydroxide (36.5 g (0.91 mole)) in a 40 weight %solution. The sodium hydroxide solution was added to the reaction via asyringe pump over a 2.5-hour period. The reaction was maintained at 80°C. for a further 8 hours. The beads were purified by removing thetoluene, washing with 1000 ml of acetone, followed by methanol, and thena 20% solution of NaOH (to remove the surfactant), and twice more withdeionized water. The beads were freeze dried for 3 days to give a finewhite powder weighing at 160 g (92% yield), and having a mean diameterof 93 μm.

Synthesis of 1,3-Diaminopropane/epichlorohydrin Crosslinked Beads(Referred to herein as: Bead-Pi-3-s)

The procedure described above was used with 1 equivalent ofepichlorohydrin.

Synthesis of Water Swollen Crosslinked Beads Prepared with1,3-Diaminopropane/epichlorohydrin in the Presence of Surfactant(Referred to herein as: Bead-Pi-5-s)

The procedure described above for the preparation of beads from1,3-diaminopropane/epichlorohydrin was reproduced exactly up to stage 2.After the reaction flask had cooled to room temperature, the stirringwas stopped. The beads settle to the bottom of the flask. The cleartoluene layer was decanted from the reaction and replaced by freshtoluene to remove unreacted epichlorohydrin. This procedure was repeated4 times and washing with a total of 3000 ml of toluene. Through out thisprocess the beads were not allowed to dry out. The total weight of thesolution was made to 756 g by adding toluene to give a 21 wt-% solutionof bead suspended in toluene.

Example 3 Preparation of Ethyl Cellulose Shell/1,3 di-amino PropaneEpichlorohydrine Crosslinked Core Particle

The beads obtained from Example 2 are spray-coated with an ethylcellulose polymer shell using a Wurster fluid bed coater 2″-4″/6″Portable Unit. The fluidized bed unit is operated so that an average 5microns thick coating is deposited on the core particles, using a 30wt-% solid aqueous emulsion (Aquacoat® ECD, FMC corp.).

Example 4 Binding Capacity in a Digestion Mimic

This procedure was used to mimic the conditions of use of a phosphatebinder drug and measure the binding characteristics of the polymer forphosphate (target solute) in the presence of other metabolites(competing solutes). A liquid meal was prepared and the meal wasartificially digested in the presence of pepsin and pancreatic juice.The sequence of addition of enzymes and the pH profile were controlledso that the digestion process was simulated down to the jejunum level.An aliquot of the digested meal mimic is centrifuged and the supernatantassayed for phosphate.

An aliquot of dried resin of weight P(gr), was mixed under gentleagitation with a fixed volume, V(ml), of a meal digest solution with aphosphate ion concentration of C_(start)(mM). After resin equilibration,the solution was decanted by centrifugation and the supernatant analyzedfor residual phosphate concentration by ionic chromatography,C_(eq)(mM). The binding capacity was calculated as BC(mmol/gr)=V.(C_(start)-C_(eq))/P.

A. Core/Shell Crosslinked Polyallylamine Particles

Procedures described in Example 1 were implemented in a library formatof 4×6 reactors, where the nature of the block copolymer was varied fromwell to well, as indicated in Tables 6-9. Entries correspond to theweight of chemicals used in each reaction well and to the phosphatebinding capacity measured in the meal digest fluid. A Selectivity Index(SI) was computed to measure the phosphate binding relative to the corematerial (i.e. crosslinked polyallylamine, Renagel). When SI was greaterthan 1, the core-shell material bound more phosphate than thecorresponding core polymer on a weight basis. The SI values for thepolymers are included in Tables 6-9.

Results are shown in Tables 6-9. Results collated in this series ofexamples show that the core-shell particles of the invention displayhigher binding for phosphate over bare, non-encapsulated particles insimulated fluid representative of the real conditions of use. Some ofthe best performing core-shell materials are then assessed in bindingphosphate in the ex-vivo aspirates from human intestinal content.

TABLE 6 Library 100411 Library: Plate 1 Unit: ul Row Col toluenedi-block s PAA s ECH di-block Pstart (mM) Peq (mM) BC (mmol/gr) SI(−) 11 281 1860 750 22.6 369_A1 7.6 2.98 1.85 1.09 1 2 281 1860 750 22.6369_A2 7.6 2.41 2.08 1.22 1 3 281 1860 750 22.6 369_A4 7.6 2.99 1.841.08 1 4 281 1860 750 22.6 369_A5 7.6 2.85 1.90 1.12 2 1 281 1860 75022.6 369_B1 7.6 3.15 1.78 1.05 2 2 281 1860 750 22.6 369_B2 7.6 2.352.10 1.23 2 3 281 1860 750 22.6 369_B4 7.6 2.76 1.94 1.14 2 4 281 1860750 22.6 369_B5 7.6 2.86 1.90 1.12 Polyallylamine 7.6 3.35 1.70 1.00core Diblock is dispensed as a 5 wt-% solution in toluene

TABLE 7 Library: Plate 1 (ID: 100482) Unit: mg Block copolymers Row Col436_B4 436_B5 436_B6 436_D4 436_D5 436_D6 Pstart m(M) Peq (mM) BC(mmol/gr) SI(−) 1 1 81.00 0.00 0.00 0.00 0.00 0.00 1 2 0.00 81.00 0.000.00 0.00 0.00 13.41 6.32 2.84 1.02 1 3 0.00 0.00 81.00 0.00 0.00 0.0013.41 6.05 2.94 1.06 1 4 0.00 0.00 0.00 81.00 0.00 0.00 13.41 5.53 3.161.14 1 5 0.00 0.00 0.00 0.00 81.00 0.00 13.41 6.33 2.83 1.02 1 6 0.000.00 0.00 0.00 0.00 81.00 13.41 4.57 3.54 1.28 2 1 40.50 0.00 0.00 0.000.00 0.00 13.41 6.66 2.70 0.97 2 2 0.00 40.50 0.00 0.00 0.00 0.00 13.415.55 3.15 1.13 2 3 0.00 0.00 40.50 0.00 0.00 0.00 13.41 5.36 3.22 1.16 24 0.00 0.00 0.00 40.50 0.00 0.00 13.41 4.98 3.37 1.22 2 5 0.00 0.00 0.000.00 40.50 0.00 13.41 4.82 3.44 1.24 2 6 0.00 0.00 0.00 0.00 0.00 40.5013.41 3.96 3.78 1.36 3 1 81.00 0.00 0.00 0.00 0.00 0.00 13.41 5.70 3.081.11 3 2 0.00 81.00 0.00 0.00 0.00 0.00 13.41 7.09 2.53 0.91 3 3 0.000.00 81.00 0.00 0.00 0.00 13.41 5.72 3.08 1.11 3 4 0.00 0.00 0.00 81.000.00 0.00 13.41 6.57 2.74 0.99 3 5 0.00 0.00 0.00 0.00 81.00 0.00 13.416.40 2.80 1.01 3 6 0.00 0.00 0.00 0.00 0.00 81.00 13.41 6.54 2.75 0.99 41 40.50 0.00 0.00 0.00 0.00 0.00 13.41 5.36 3.22 1.16 4 2 0.00 40.500.00 0.00 0.00 0.00 13.41 6.07 2.94 1.06 4 3 0.00 0.00 40.50 0.00 0.000.00 13.41 5.51 3.16 1.14 4 4 0.00 0.00 0.00 40.50 0.00 0.00 13.41 4.213.68 1.33 4 5 0.00 0.00 0.00 0.00 40.50 0.00 13.41 4.96 3.38 1.22 4 60.00 0.00 0.00 0.00 0.00 40.50 13.41 4.58 3.53 1.27 Polyallylamine 13.416.48 2.77 1.00 core Constant reactor composition (mg) toluene PAA H2ONaOH EPH 1768.95 270.00 511.16 28.84 40.05 Row 1 & 2: 30 sec. sonicationtime Row 3 & 4: 90 sec. sonication time

TABLE 8 Library Sample Block Copolymer BC(mmol/gr) IC(−) 100516 100516A1 100436 A1 3.02 1.25 100516 100516 A2 100436 A2 3.44 1.43 100516100516 A3 100436 A3 3.33 1.38 100516 100516 A4 100436 A4 3.01 1.25100516 100516 A5 100436 A5 3.29 1.37 100516 100516 A6 100436 A6 3.521.46 100516 100516 B1 100436 B1 3.30 1.37 100516 100516 B2 100436 B23.60 1.49 100516 100516 B3 100436 B3 3.38 1.40 100516 100516 B4 100436B4 3.52 1.46 100516 100516 B5 100436 B5 3.74 1.55 100516 100516 B6100436 B6 3.32 1.38 100516 100516 C1 100436 C1 3.89 1.61 100516 100516C2 100436 C2 3.54 1.47 100516 100516 C3 100436 C3 2.75 1.14 100516100516 C4 100436 C4 3.57 1.48 100516 100516 C5 100436 C5 3.53 1.47100516 100516 C6 100436 C6 2.64 1.09 100516 100516 D1 100436 D1 3.781.57 100516 100516 D2 100436 D2 3.57 1.48 100516 100516 D3 100436 D33.12 1.29 100516 100516 D4 100436 D4 3.40 1.41 100516 100516 D5 100436D5 3.75 1.55 Polyallylamine core 2.41 1.00 Constant reactor composition(mg) toluene PAA H₂O NaOH EPH Block cop. 1768.95 270.00 511.16 28.8440.05 40.05 30 sec. sonication time Library 100517 is identical to100516 with the exception that the beads were further treated with HCl1M for 6 hrs @ 60° C. to deprotect the terbutylacrylate groups intoacrylic acid groups.

TABLE 9 Library Sample Block Copolymer BC(mmol/gr) IC(−) 100517 100517A1 100436 A1 3.04 1.26 100517 100517 A2 100436 A2 3.30 1.37 100517100517 A3 100436 A3 3.26 1.35 100517 100517 A4 100436 A4 3.35 1.39100517 100517 A5 100436 A5 2.86 1.18 100517 100517 B1 100436 B1 3.221.33 100517 100517 B2 100436 B2 3.60 1.49 100517 100517 B3 100436 B33.64 1.51 100517 100517 B4 100436 B4 3.58 1.48 100517 100517 B5 100436B5 3.82 1.58 100517 100517 B6 100436 B6 3.62 1.50 100517 100517 C1100436 C1 3.52 1.46 100517 100517 C2 100436 C2 3.37 1.39 100517 100517C3 100436 C3 2.86 1.18 100517 100517 C4 100436 C4 3.24 1.34 100517100517 C5 100436 C5 3.34 1.38 100517 100517 C6 100436 C6 2.22 0.92100517 100517 D1 100436 D1 3.24 1.34 100517 100517 D2 100436 D2 3.171.31 100517 100517 D3 100436 D3 3.21 1.33 100517 100517 D4 100436 D43.32 1.38 100517 100517 D5 100436 D5 3.02 1.25 Polyallyamine core 2.421.00 Constant reactor composition (mg) toluene PAA H₂O NaOH EPH Blockcop. 1768.95 270.00 511.16 28.84 40.05 40.05 30 sec. sonication timeLibrary 100517 is identical to 100516 with the exception that the beadswere further treated with HCl 1 M for 6 hrs @ 60° C. to deprotect theterbutylacrylate groups into acrylic acid groups.B. Core/Shell Crosslinked 1,3-diaminopropane/epichlorohydrine Particles

Procedures described in Example 2 were implemented in a library formatof 4×6 reactors, where the nature of the polymer was varied from well towell, as indicated in Tables 11-18. Entries in the Tables correspond tothe weight of chemicals used in each reaction well, and to the phosphatebinding capacity measured in the meal digest fluid. A Selectivity Index(SI) was computed as described above. The SI values for the polymers areincluded in Tables 11-18.

Each example comprised a library of 22 core-shell materials and one corematerial taken as a reference. The core materials are beads preparedfrom crosslinked 1,3-diaminopropane/epichlorohydrine as shown in Example2 (bead 4-s, bead 3-s, and bead 5-s). They were used either as a drypowder (bead 4-s, bead 3-s) or as a slurry in toluene (bead 5-s). Thecore-shell particles were prepared in semi-continuous reactors arrangedin a 4×6 library format. Each reactor had a 3 ml volume, wasmagnetically stirred, and temperature-controlled. In a typicalprocedure, the beads were first dispensed, followed by the addition ofthe selected solvent under magnetic agitation. The reaction temperaturewas set to 60° C. The shell materials were then robotically dispensedfor 4 hours and the 24 reactions kept another 12 hours at the settemperature. The library was then cooled down to ambient temperature andthe content of the reactors transferred to 15 ml vials. The core-shellbeads were then washed repeatedly with a fresh volume of the samesolvent used during the shell coupling reaction, then with isopropanol,and finally with de-ionized water. The particles were finallylyophilized.

The chemical structures of the shell materials used are shown in Table10.

TABLE 10 Label Name CAS # Structure MW (g/mol) Shell-AH-1POLY(METHYLVINYL ETHER-ALT-MALEIC ANHYDRIDE)

MW ~20,000 Shell-AH-2 POLY(METHYLVINYL ETHER-ALT-MALEIC ANHYDRIDE)

MW ~50,000 Shell-AH-3 POLY(METHYLVINYL ETHER-ALT-MALEIC ANHYDRIDE)9011-16-9

Mn. ~80,000Mw. ~216,000 Shell-AH-4 POLY(STYRENE-MALEIC MW = 1600ANHYDRIDE) 50:50 (molar) Shell-AH-5 POLY(STYRENE-MALEIC MW = 1900ANHYDRIDE) 75:25 (molar) Shell-AH-6 POLY(STYRENE-co-MALEIC 26762-29-8 Mn= 1600 ANHYDRIDE), CUMENE TERMINATED Shell-AH-7 POLY(STYRENE-co-MALEIC26762-29-8 Mn = 1700 ANHYDRIDE), CUMENE TERMINATED Shell-AH-8POLY(STYRENE-co-MALEIC 160611-46-1 Mn = 2300 ANHYDRIDE). PARTIAL ISOCTYLFW = 658.8 ESTER, CUMENE TERMINATED Shel-AH-9 POLY(STYRENE-co-MALEIC160611-50-7 Av. Mn = 2500 ANHYDRIDE), PARTIAL 2- BUTOXYETHYLESTER,CUMENE TERMINATED Shell-AH-10 POLY(ETHYLENE-co-ETHYL 41171-14-6 /ACRYLATE-co-MALEIC ANHYDRIDE) Shell-AH-11 POLY(STYRENE-co-MALEIC160611-48-3 Mn ~1900 ANHYDRIDE), PARTIAL PROPYL ESTER, CUMENE TERMINATEDShell-AH-12 POLYETHYLENE-graft-MALEIC 106343-08-2 FW ~154.2 ANHYDRIDEShell-AH-13 POLYISOPRENE-graft-MALEIC 139948-75-7 FW = 234.3 ANHYDRIDEMn ~25000 Shell-AH-14 POLY(ETHYLENE-co-BUTYL 64652-60-4 FW = 268.3ACRYLATE-co-MALEIC ANHYDRIDE) Shell-CI-1 2-CHLOROETHANESULFONICACIDSODIUM SALT 15484-44-3

166.56 Shell-CI-2 3-CHLORO-2-HYDROXYPROPANESULFONICACID SODIUM SALT126-83-0

196.59 Shell-Mc-1 DIETHYLENE GLYCOLDIACRYLATE 4074-88-8

214.22 Shell-Mc-2 POLY(ETHYLENE GLYCOL)DIACRYLATE 26570-49-8

Mn. ~700 Shell-Mc-3 POLY(ETHYLENE-co- 51541-08-3 FW = 256.3METHACRYLATE-co-GLYCIDYL METHACRYLATE) Shell-EP-12-(3,4-EPOXYCYCLOHEXYL)-ETHYLTRIETHOXYSILANE

288.5 Shell-EP-2 Shell-EP-3 Shell-EP-4 Shell-EP-5 Shell-EP-6 POLY(ETHYLGLYCOL)DIGLYCIDYL ETHERPOLY(ETHYL GLYCOL) (200)DIGLYCIDYLETHERPOLY(ETHYL GLYCOL) (400)DIGLYCIDYL ETHERPOLY(ETHYL GLYCOL)(600)DIGLYCIDYL ETHERPOLY(ETHYL GLYCOL) (1000)DIGLYCIDYL ETHER26403-72-5 26403-72-5 26403-72-5 26403-72-5 26403-72-5

526.6 200 400 600 1000 Shell-EP-7 1,3-BUTADIENE DIEPOXIDE 1464-53-5

86.09 Shell-EP-8 3-(1H,1H,7H-DODECAFLUOROHEPTYLOXY)-1,2-EPOXYPROPANE799-34-8

388.15 Shell-EP-9 GLYCIDYL 4-NONYLPHENYLETHER 6178-32-1

276.42 Shell-EP-10 POLY(PROPYLENE GLYCOL)DIGLYCIDYL ETHER 26142-30-3

640 Shell-EP-11 GLYCIDYL HEXADECYL ETHER 15965-99-8

298.51 Shell-EP-12bis 2-[(4-NITROPHENOXY)METHYL]OXIRANE 5255-75-4

195.18 Shell-EP-12 POLY(BISPHENOL A-co- 25036-25-3 FW = 487.0EPICHLOROHYDRIN), GLYCICYL Mn ~355 END-CAPPED Shell-EP-13 POLY(BISPHENOLA-co- FW = 487.0 EPICHLOROHYDRIN), GLYCICYL Mn ~1075 END-CAPPEDShell-EP-14 POLY(BISPHENOL A-co- Mn ~1750 EPICHLOROHYDRIN), GLYCICYLEND-CAPPED Shell-EP-15 POLY(BISPHENOL A-co- / EPICHLOROHYDRIN), GLYCICYLEND-CAPPED Shell-EP-16 POLY(o-CRESYL GLYCIDYL 29690-82-2 FW = 194.2ETHER)-co-FORMALDEHYDE) Mn ~540 Shell-EP-17 POLY(o-CRESYL GLYCIDYL29690-82-3 FW = 194.2 ETHER)-co-FORMALDEHYDE) Mn ~1270 Shell-EP-18POLY(ETHYLENE-co-GLYCIDYL 26061-90-5 FW = 170.2 METHACRYLATE)Shell-EP-19 BISPHENOL DIGLYCIDYL ETHER 1675-54-3 Shell-EP-20POLY(DIMETHYLSILOXANE) 130167-23-6 FW = 282.5 DIGLYCIDYL TERMINATED EW~490 Shell-EP-21 POLY[(PHENYL GLYCIDYL ETHER)- / FW = 180.2co-FORMALDEHYDE] Mn ~345 Shell-EP-22 POLY[(PHENYL GLYCIDYL ETHER)-28064-14-4 FW = 180.2 co-FORMALDEHYDE] Mn ~570 Shell-EP-23 POLY[(PHENYLGLYCIDYL ETHER)- 119345-05-0 FW = 286.4 co-DICYCLOPENTADIENE] Mn ~490Shell-EP-24 POLY(EPICHLOROHYDRIN-co- 26587-37-1 ETHYLENE OXIDE-co-ALLYGLYCIDYL ETHER Shell-EP-25 CASTOR OIL GLYCIDYL ETHER 74398-71-3Shell-EP-26 TETRAPHENYLOLETHANE / GLYCIDYL ETHER Shell-EP-27 EPONRESINS - 828 /

Results are shown in Tables 11-18. Results collated in this series ofexample show that the core-shell particles of the invention displayhigher rate of binding for phosphate over bare, non-encapsulatedparticles in simulated fluid representative of the real conditions ofuse.

TABLE 11 library Shell- Shell- Shell- Shell- bead- bead- bead- ID rowcolumn NaOH EP-10 EP-12 EP-16 Mc-3 pi-3 pi-4 pi-5 toluene waterBC(mmol/gr) SI(−) 100433 A 1 0.00 1.25 23.75 0.41 0.76 100433 A 2 0.001.25 23.75 0.46 0.85 100433 A 3 0.00 1.25 23.75 0.43 0.81 100433 A 40.00 1.25 23.75 0.40 0.74 100433 A 5 0.00 1.25 23.75 0.40 0.75 100433 A6 0.00 1.25 23.75 0.48 0.90 100433 B 1 0.00 1.25 23.75 0.50 0.93 100433B 2 0.00 1.25 23.75 0.51 0.94 100433 B 3 0.00 1.25 23.75 0.58 1.07100433 B 4 0.00 1.25 23.75 0.64 1.19 100433 B 5 0.00 1.25 23.75 0.380.70 100433 B 6 0.00 1.25 23.75 0.35 0.66 100433 C 1 0.10 1.25 23.660.29 0.55 100433 C 2 0.10 1.25 23.66 0.60 1.12 100433 C 3 0.10 1.2523.66 0.49 0.91 100433 C 4 0.10 1.25 23.66 0.70 1.30 100433 C 5 0.101.25 23.66 0.44 0.82 100433 C 6 25.00 0.54 1.00 100433 D 1 1.25 23.750.56 1.03 100433 D 2 1.25 23.75 0.63 1.18 100433 D 3 1.25 23.75 0.500.94 100433 D 4 1.25 23.75 0.57 1.06 100433 D 5 1.25 23.75 0.43 0.80100461 A 1 24.00 120.00 2256.00 1.47 1.08 100461 A 2 56.40 141.002622.60 1.46 1.07 100461 A 3 95.88 159.80 2940.32 1.45 1.07 100461 A 4124.00 155.00 2821.00 1.48 1.09 100461 A 5 108.60 108.60 1954.80 1.401.03 100461 B 1 32.92 164.60 3094.48 1.26 0.92 100461 B 2 59.04 147.602745.36 1.51 1.11 100461 B 3 96.24 160.40 2951.36 1.48 1.09 100461 B 4129.12 161.40 2937.48 1.46 1.07 100461 B 5 136.10 136.10 2449.80 1.571.15 100461 C 1 33.18 165.90 3118.92 1.38 1.02 100461 C 2 54.20 135.502520.30 1.39 1.02 100461 C 3 90.36 150.60 2771.04 1.53 1.13 100461 C 493.36 116.70 2123.94 1.35 1.00 100461 C 5 148.70 148.70 2676.60 1.521.12 100461 C 6 165.10 1.36 1.00 100461 D 1 32.56 162.80 3060.64 1.371.01 100461 D 2 75.16 187.90 3494.94 1.24 0.91 100461 D 3 65.94 109.902022.16 1.44 1.06 100461 D 4 100.08 125.10 2276.82 1.49 1.10 100461 D 5166.30 166.30 2993.40 1.47 1.08 100462 A 1 24.21 121.02 2275.23 1.511.13 100462 A 2 44.65 111.62 2076.04 1.54 1.15 100462 A 3 64.15 106.911967.16 1.45 1.08 100462 A 4 76.94 96.18 1750.48 1.46 1.09 100462 A 5109.49 109.49 1970.89 1.53 1.14 100462 B 1 22.44 112.20 2109.42 1.491.11 100462 B 2 45.46 113.65 2113.93 1.41 1.05 100462 B 3 67.79 112.982078.83 1.55 1.16 100462 B 4 89.96 112.46 2046.68 1.55 1.16 100462 B 5102.12 102.12 1838.21 1.51 1.12 100462 C 1 22.22 111.09 2088.49 1.691.26 100462 C 2 42.97 107.44 1998.31 1.76 1.31 100462 C 3 59.03 98.391810.28 1.74 1.30 100462 C 4 86.34 107.92 1964.13 1.59 1.18 100462 C 5108.15 108.15 1946.70 1.48 1.10 100462 C 6 100.30 377.30 1.34 1.00100462 D 1 20.03 100.15 1882.80 1.60 1.20 100462 D 2 38.24 95.59 1778.011.80 1.34 100462 D 3 56.73 94.54 1739.57 1.75 1.31 100462 D 4 85.36106.70 1941.96 2.00 1.49 100462 D 5 103.19 103.19 1857.49 2.06 1.54

TABLE 12 library Shell- Shell- Shell- Shell- bead- ethyl ID row columnAH-11 AH-9 EP-8 IC-1 pi-5 acetate methanol toluene water BC(mmol/gr)SI(−) 100468 A 1 31.70 158.50 2979.80 1.48 0.96 100468 A 2 76.28 190.703547.02 1.63 1.06 100468 A 3 106.20 177.00 3256.80 1.56 1.01 100468 A 4133.20 166.50 3030.30 1.50 0.98 100468 A 5 123.40 123.40 2221.20 1.530.99 100468 B 1 28.06 140.30 2637.64 1.70 1.10 100468 B 2 52.48 131.202440.32 1.60 1.04 100468 B 3 84.48 140.80 2590.72 1.70 1.10 100468 B 4106.00 132.50 2411.50 1.73 1.12 100468 B 5 146.40 146.40 2635.20 1.701.11 100468 C 1 28.96 144.80 2722.24 1.53 0.99 100468 C 2 50.20 125.502334.30 1.45 0.94 100468 C 3 93.48 155.80 2866.72 1.48 0.96 100468 C 4140.24 175.30 3190.46 1.37 0.89 100468 C 5 188.80 188.80 3398.40 1.190.78 100468 C 6 221.10 1.54 1.00 100468 D 1 41.38 206.90 3889.72 1.440.94 100468 D 2 61.84 154.60 2875.56 1.49 0.97 100468 D 3 109.62 182.703361.68 1.46 0.95 100468 D 4 117.04 146.30 2662.66 1.45 0.94 100468 D 5148.20 148.20 2667.60 1.46 0.95

TABLE 13 library Shell- Shell- Shell- Shell- Shell- bead- ethyl ID rowcolumn EP-1 EP-10 EP-12bis EP-13 Mc-2 pi-5 acetate toluene BC(mmol/gr)SI(−) 100473 A 1 94.02 156.70 2883.28 1.68 1.10 100473 A 2 89.82 149.702754.48 1.52 0.99 100473 A 3 114.12 190.20 3499.68 1.57 1.02 100473 A 495.76 159.60 2936.64 1.47 0.96 100473 A 5 81.12 135.20 2487.68 1.47 0.96100473 B 1 98.52 164.20 3021.28 1.49 0.97 100473 B 2 98.76 164.603028.64 1.44 0.94 100473 B 3 109.80 183.00 3367.20 1.37 0.89 100473 B 492.70 154.50 2842.80 1.41 0.92 100473 B 5 114.24 190.40 3503.36 1.460.96 100473 C 1 90.18 150.30 2765.52 1.46 0.95 100473 C 2 90.00 150.002760.00 1.43 0.94 100473 C 3 82.74 137.90 2537.36 1.41 0.92 100473 C 499.12 165.20 3039.68 1.35 0.88 100473 C 5 106.32 177.20 3260.48 1.360.89 100473 C 6 212.40 1.53 1.00 100473 D 1 90.84 151.40 2785.76 1.240.81 100473 D 2 100.68 167.80 3087.52 1.42 0.93 100473 D 3 113.82 189.703490.48 1.45 0.95 100473 D 4 105.36 175.60 3231.04 1.46 0.95 100473 D 590.30 150.50 2769.20 1.51 0.99 100474 A 1 90.18 150.30 2765.52 1.64 1.19100474 A 2 86.88 144.80 2664.32 1.42 1.03 100474 A 3 101.94 169.903126.16 1.26 0.91 100474 A 4 100.92 168.20 3094.88 1.36 0.99 100474 A 594.32 157.20 2892.48 1.47 1.07 100474 B 1 88.02 146.70 2699.28 1.36 0.98100474 B 2 95.70 159.50 2934.80 1.37 0.99 100474 B 3 89.88 149.802756.32 1.48 1.07 100474 B 4 109.02 181.70 3343.28 1.40 1.02 100474 B 586.46 144.10 2651.44 1.43 1.04 100474 C 1 84.60 141.00 2594.40 1.42 1.03100474 C 2 89.52 149.20 2745.28 1.45 1.05 100474 C 3 84.72 141.202598.08 1.48 1.07 100474 C 4 112.02 186.70 3435.28 1.44 1.04 100474 C 5104.58 174.30 3207.12 1.42 1.03 100474 C 6 216.20 1.38 1.00 100474 D 194.50 157.50 2898.00 1.48 1.07 100474 D 2 110.40 184.00 3385.60 1.421.03 100474 D 3 102.18 170.30 3133.52 1.72 1.25 100474 D 4 87.84 146.402693.76 1.54 1.12 100474 D 5 97.86 163.10 3001.04 1.53 1.11 100480 A 129.76 148.80 2797.44 1.32 0.95 100480 A 2 77.96 194.90 3625.14 1.18 0.85100480 A 3 102.24 170.40 3135.36 0.95 0.68 100480 A 4 133.28 166.603032.12 0.79 0.57 100480 A 5 143.90 143.90 2590.20 0.80 0.57 100480 B 132.08 160.40 3015.52 0.99 0.71 100480 B 2 69.20 173.00 3217.80 1.14 0.82100480 B 3 112.20 187.00 3440.80 1.24 0.89 100480 B 4 130.72 163.402973.88 1.35 0.96 100480 B 5 155.80 155.80 2804.40 1.12 0.80 100480 C 131.16 155.80 2929.04 1.25 0.90 100480 C 2 56.00 140.00 2604.00 1.30 0.93100480 C 3 95.16 158.60 2918.24 1.45 1.03 100480 C 4 157.76 197.203589.04 1.56 1.12 100480 C 5 162.60 162.60 2926.80 1.55 1.11 100480 C 6149.00 1.40 1.00 100480 D 1 29.76 148.80 2797.44 1.44 1.03 100480 D 273.68 184.20 3426.12 1.39 0.99 100480 D 3 93.78 156.30 2875.92 1.39 1.00100480 D 4 131.36 164.20 2988.44 1.34 0.96 100480 D 5 145.10 145.102611.80 1.31 0.94

TABLE 14 library Shell- Shell- Shell- Shell- bead- bead- ethyl ID rowcolumn EP-11 EP-12bis EP-8 EP-9 pi-4 pi-5 acetate methanol tolueneBC(mmol/gr) SI(−) 100484 A 1 3.41 170.70 3239.89 1.89 1.36 100484 A 210.50 161.50 3058.00 1.78 1.29 100484 A 3 20.14 183.10 3458.76 1.82 1.31100484 A 4 21.39 138.00 2600.61 1.36 0.98 100484 A 5 32.66 163.303070.04 1.29 0.93 100484 B 1 3.17 158.30 3004.53 1.85 1.33 100484 B 210.22 157.20 2976.58 1.93 1.39 100484 B 3 19.91 181.00 3419.09 1.83 1.32100484 B 4 25.05 161.60 3045.35 1.89 1.36 100484 B 5 29.72 148.602793.68 1.91 1.38 100484 C 1 2.99 149.50 2837.51 2.09 1.51 100484 C 210.04 154.40 2923.56 1.95 1.41 100484 C 3 19.93 181.20 3422.87 1.83 1.32100484 C 4 25.76 166.20 3132.04 1.80 1.30 100484 C 5 30.60 153.002876.40 1.85 1.33 100484 C 6 211.50 1.39 1.00 100484 D 1 3.07 153.302909.63 1.39 1.00 100484 D 2 12.33 189.70 3591.97 1.88 1.35 100484 D 318.22 165.60 3128.18 1.76 1.27 100484 D 4 27.27 175.90 3314.84 1.77 1.27100484 D 5 32.16 160.80 3023.04 1.83 1.32 100485 A 1 3.05 152.36 2318.55573.15 1.29 0.92 100485 A 2 9.71 149.33 2265.81 561.77 1.03 0.73 100485A 3 17.53 159.33 2410.31 599.37 1.04 0.74 100485 A 4 25.50 164.512481.38 618.89 100485 A 5 35.53 177.66 2671.67 668.34 0.89 0.63 100485 B1 3.34 167.03 3170.31 1.39 0.98 100485 B 2 8.54 131.44 2488.80 0.69 0.49100485 B 3 16.87 153.38 2897.42 1.12 0.80 100485 B 4 23.64 152.482873.50 1.49 1.06 100485 B 5 33.68 168.42 3166.30 1.55 1.10 100485 C 13.06 152.78 2899.67 1.31 0.93 100485 C 2 9.44 145.19 2749.25 1.50 1.06100485 C 3 16.51 150.09 2835.14 1.49 1.05 100485 C 4 24.86 160.403022.70 1.42 1.01 100485 C 5 28.96 144.82 2722.54 1.36 0.96 100485 C 6139.29 524.01 1.41 1.00 100485 D 1 3.02 150.99 2865.79 1.45 1.03 100485D 2 10.35 159.29 3016.06 1.48 1.05 100485 D 3 22.61 205.53 3882.41 1.020.73 100485 D 4 23.91 154.29 2907.54 1.24 0.88 100485 D 5 28.81 144.062708.33 0.82 0.58

TABLE 15 Library: Plate 1 (ID: 100500) Unit: mg Row Col bead-pi-4toluene Shell-EP-12 BC(mmol/gr) SI(−) 1.00 1.00 171.99 3233.41 34.401.31 1.26 1.00 2.00 144.02 2678.73 57.61 0.93 0.90 1.00 3.00 152.572807.20 91.54 1.15 1.10 1.00 4.00 156.60 2850.07 125.28 0.71 0.68 1.005.00 156.32 2813.83 156.32 0.78 0.75 2.00 1.00 156.72 2946.39 31.34 1.391.33 2.00 2.00 156.74 2915.44 62.70 1.61 1.54 2.00 3.00 154.35 2840.0492.61 2.08 1.99 2.00 4.00 154.35 2809.17 123.48 0.53 0.50 2.00 5.00153.59 2764.69 153.59 0.60 0.57 2.00 6.00 140.87 529.93 0.00 0.89 0.863.00 1.00 140.18 2635.29 28.04 1.15 1.11 3.00 2.00 148.66 2765.06 59.461.84 1.77 3.00 3.00 142.44 2620.95 85.47 1.72 1.65 3.00 4.00 149.002711.71 119.20 2.27 2.18 3.00 5.00 137.05 2466.83 137.05 0.73 0.70 3.006.00 153.03 575.67 0.00 1.04 1.00 4.00 1.00 141.54 2660.95 28.31 1.241.19 4.00 2.00 148.47 2761.54 59.39 1.60 1.54 4.00 3.00 130.16 2394.9178.09 1.17 1.12 4.00 4.00 137.76 2507.23 110.21 1.37 1.31 4.00 5.00140.22 2523.91 140.22 0.96 0.93

TABLE 16 Library: Plate 2 (ID: 100501) Unit: mg bead- Row Col pi-4toluene Shell-EP-16 BC(mmol/gr) SI(−) 1.00 1.00 150.72 2833.48 30.140.94 0.87 1.00 2.00 150.15 2792.79 60.06 1.22 1.12 1.00 3.00 143.912648.00 86.35 1.33 1.23 1.00 4.00 153.43 2792.35 122.74 1.81 1.67 1.005.00 154.94 2788.88 154.94 1.01 0.94 2.00 1.00 150.32 2825.98 30.06 1.000.93 2.00 2.00 149.12 2773.65 59.65 1.44 1.33 2.00 3.00 149.18 2744.9989.51 1.93 1.78 2.00 4.00 147.19 2678.84 117.75 1.49 1.38 2.00 5.00147.82 2660.74 147.82 0.92 0.85 2.00 6.00 147.27 554.03 0.00 0.92 0.853.00 1.00 140.45 2640.42 28.09 0.96 0.88 3.00 2.00 141.39 2629.91 56.561.50 1.39 3.00 3.00 140.51 2585.40 84.31 0.96 0.89 3.00 4.00 149.002711.71 119.20 1.76 1.63 3.00 5.00 131.23 2362.12 131.23 0.00 3.00 6.00150.21 565.09 0.00 1.08 1.00 4.00 1.00 149.21 2805.05 29.84 0.98 0.914.00 2.00 151.98 2826.77 60.79 1.33 1.23 4.00 3.00 155.36 2858.59 93.211.40 1.30 4.00 4.00 173.78 3162.71 139.02 2.00 1.85 4.00 5.00 144.522601.40 144.52 2.10 1.94

TABLE 17 Library: Plate 2 (ID: 100487) Unit: mg Row Col bead-pi-4toluene Shell-EP-9 Shell-EP-2 Shell-EP-14 ethyl acetate BC(mmol/gr)SI(−) 1.00 1.00 164.43 3091.28 8.22 24.66 0.00 0.00 0.66 0.87 1.00 2.00145.70 2709.98 14.57 43.71 0.00 0.00 0.27 0.36 1.00 3.00 147.57 2715.2322.14 66.41 0.00 0.00 0.26 0.35 1.00 4.00 149.25 2716.30 29.85 89.550.00 0.00 0.54 0.71 1.00 5.00 150.19 2703.46 37.55 112.64 0.00 0.00 0.460.60 2.00 1.00 143.43 2696.48 9.56 19.12 0.00 0.00 0.57 0.76 2.00 2.00134.19 2495.93 17.89 35.78 0.00 0.00 0.57 0.76 2.00 3.00 137.07 2522.0327.41 54.83 0.00 0.00 0.56 0.74 2.00 4.00 134.36 2445.32 35.83 71.660.00 0.00 0.53 0.70 2.00 5.00 133.22 2398.03 44.41 88.82 0.00 0.00 0.510.68 3.00 1.00 136.77 2386.69 6.84 0.00 20.52 184.64 0.50 0.66 3.00 2.00151.94 2415.77 15.19 0.00 45.58 410.22 1.14 1.52 3.00 3.00 150.822164.30 22.62 0.00 67.87 610.83 1.50 1.98 3.00 4.00 155.74 1993.42 31.150.00 93.44 840.97 1.12 1.48 3.00 5.00 157.73 1774.47 39.43 0.00 118.301064.68 0.94 1.24 3.00 6.00 153.01 575.59 0.00 0.00 0.00 0.00 0.75 1.004.00 1.00 155.30 2733.19 10.35 0.00 20.71 186.35 0.50 0.67 4.00 2.00150.36 2435.83 20.05 0.00 40.10 360.86 1.03 1.36 4.00 3.00 153.952278.47 30.79 0.00 61.58 554.22 1.36 1.80 4.00 4.00 151.60 2031.43 40.430.00 80.85 727.68 1.38 1.83 4.00 5.00 151.56 1818.68 50.52 0.00 101.04909.34 1.24 1.64

TABLE 18 Library: Plate 1 (ID: 100486) Unit: mg Row Col bead-pi-4toluene Shell-EP-9 Shell-EP-11 Shell-EP-2 Shell-EP-14 ethyl acetateBC(mmol/gr) SI(−) 1.00 1.00 138.29 2599.76 27.66 0.00 0.00 0.00 0.000.69 0.95 1.00 2.00 150.40 2797.48 60.16 0.00 0.00 0.00 0.00 0.62 0.851.00 3.00 152.42 2804.49 91.45 0.00 0.00 0.00 0.00 0.59 0.82 1.00 4.00157.56 2867.65 126.05 0.00 0.00 0.00 0.00 0.44 0.61 1.00 5.00 140.222523.91 140.22 0.00 0.00 0.00 0.00 0.40 0.56 2.00 1.00 153.01 2876.510.00 30.60 0.00 0.00 0.00 0.40 0.55 2.00 2.00 154.37 2871.30 0.00 61.750.00 0.00 0.00 0.32 0.44 2.00 3.00 162.50 2989.96 0.00 97.50 0.00 0.000.00 0.43 0.60 2.00 4.00 150.26 2734.64 0.00 120.20 0.00 0.00 0.00 0.360.49 2.00 5.00 139.04 2502.74 0.00 139.04 0.00 0.00 0.00 0.44 0.61 3.001.00 157.29 2957.05 0.00 0.00 31.46 0.00 0.00 0.29 0.40 3.00 2.00 153.912862.71 0.00 0.00 61.56 0.00 0.00 0.33 0.45 3.00 3.00 150.84 2775.510.00 0.00 90.51 0.00 0.00 0.40 0.55 3.00 4.00 162.02 2948.67 0.00 0.00129.61 0.00 0.00 0.35 0.49 3.00 5.00 154.41 2779.43 0.00 0.00 154.410.00 0.00 0.38 0.53 3.00 6.00 161.45 607.35 0.00 0.00 0.00 0.00 0.000.72 1.00 4.00 1.00 156.49 2660.36 0.00 0.00 0.00 31.30 281.69 0.60 0.834.00 2.00 157.65 2364.71 0.00 0.00 0.00 63.06 567.53 1.38 1.91 4.00 3.00157.12 2042.59 0.00 0.00 0.00 94.27 848.46 1.46 2.02 4.00 4.00 153.241685.61 0.00 0.00 0.00 122.59 1103.31 1.37 1.89 4.00 5.00 155.00 1395.010.00 0.00 0.00 155.00 1395.01 1.20 1.66

Example 5

Binding Capacity Measurements in a Non Interfering Buffer

An aliquot of dried resin of weight P(gr), is mixed under gentleagitation with a fixed volume, V(ml), of a phosphate ion solution ofconcentration C_(start)(mM) buffered at pH 6.5. After resinequilibration, the solution is decanted by centrifugation and thesupernatant analyzed for residual phosphate concentration by ionicchromatography, C_(eq)(mM). The binding capacity is calculated as BC(mmol/gr)=V. (C_(start)-C_(eq))/P.

Binding Capacity in a Ex-vivo Aspirates

In this example healthy patients are given a meal of the samecomposition as the one prepared for the digestion mimic and aliquots ofchyme are then sampled using a tube placed in the lumen of the smallintestine.

Normal subjects are intubated with a double lumen polyvinyl tube, with amercury weighted bag attached to the end of the tube to facilitatemovement of the tube into the small intestine. One aspiration apertureof the double lumen tube is located in the stomach and the otheraperture is at the Ligament of Treitz (in the upper jejunum). Placementtakes place with the use of fluoroscopy.

After correct tube is placed, 550 mL of a liquid standard test meal(supplemented with a marker, polyethylene glycol (PEG)−2 g/550 mL) isinfused into the stomach through the gastric aperture at a rate of 22 mLper minute. It requires approximately 25 minutes for the entire meal toreach the stomach. This rate of ingestion simulates the duration of timerequired to eat normal meals.

Jejunal chyme is aspirated from the tube whose lumen is located at theLigament of Treitz. This fluid is collected continuously during30-minute intervals for a two and a half hour period. This results in 5specimens that are mixed, measured for volume, and lyophilized.

The phosphate binding procedure is identical to the one describedearlier with the non-interfering buffer experiment, except that theex-vivo aspirate liquid is used (after reconstitution of thefreeze-dried material in the proper amount of de-ionized water). Thebinding capacity in the ex-vivo aspirate (VA) is calculated in the sameway. Core-shell compositions bind more phosphate than the correspondingcore component.

Example 6 Method of Selection of Semi-permeable Membrane with HighPotassium Binding Selectivity Over Magnesium and Calcium

This protocol describes a method to optimize polymeric materials withregards to their ion permselectivity characteristics, which then can beused as the shell component for the making of potassium selectivecore-shell ion-exchange particles.

Polymer Synthesis and Membrane Preparation:

Polymeric membrane materials with different compositions were preparedby radical copolymerization of DBA (N,N′-dibutyl acrylamide) and DEAEMA(N,N′-diethylaminoethylmethacrylate) in a glove box using miniaturizedreactors in a library format. AIBN was used as the initiator and ethanolas the solvent. Polymers were isolated by precipitation into water,freeze-dried, and characterized by GPC and H-NMR. The composition of thepolymer (DBA mol %) ranges from 30% to 70% and molecular weight rangesfrom 200K to 300K as shown below:

TABLE 19 Polymer ID 101224 D1 D2 D3 D4 D5 D6 Mn (×10³) 327 326 322 285240 217 Mw (×10³) 584 563 520 467 411 340 PDI 1.78 1.73 1.61 1.64 1.711.56 Composition 31.2 37.1 48.5 56.1 64.4 68.5 (DBA, mol %)

Polymer membranes were prepared by casting a 2-wt % toluene solution ofDBA-co-DEAEMA onto a regenerated cellulose dialysis membrane (RCmembrane with MWCO of 14 K). After toluene was evaporated, a polymermembrane was formed on the top of dialysis membrane. A compositemembrane of polymer membrane and RC membrane was thus prepared.

Permeability Study on Cations

The composite membrane was first clamped onto a glass tube with diameterof 13 mm, and then immersed into a 2 L of donor solution of cations. Thetube was filled with 10 ml of acceptor solution (lactose solution withthe same osmolality as the donor solution (240 mM)). The acceptorsolution was sampled at a specified time interval and analyzed by ionchromatography. See FIG. 3.

Donor solution was prepared by mixing the aqueous solution of NaCl, KCl,CaCl₂.2H₂O, and MgSO₄.7H₂O. The solution was buffered to pH 6 by using14 mM of MES (2-[N-morpholine]ethanesulfonic acid] solution. Theconcentrations of different cations determined by IC were as follows:[Na⁺], 40.46 mM; [K⁺], 31.44 mM; [Mg²⁺], 33.25 mM; [Ca²⁺], 22.324 mM.

Determination of the permeability coefficient (P) of different cations:As mentioned in the measurement set-up, the acceptor solution wassampled at a specific time interval and analyzed by IC. Assuming aFick's first law of diffusion, P is readily obtained by linearization ofthe data, following a method of calculation reported in equation 1 in G.Van den Mooter, C. Samyn, and R. Kinget, International Journal ofPharmaceutics, 111, 127-136(1994). The permeability coefficients ofdifferent cations were thus calculated from the slope from this linearrelationship.

$\begin{matrix}{{- {\ln\left( \frac{C_{o} - C_{a}}{C_{o}} \right)}} = {\frac{PS}{Va}t}} & {{Equation}\mspace{14mu} 1}\end{matrix}$Where C_(o) is the initial concentration of the solute in the donorcompartment and C_(a) the concentration in the acceptor compartment attime t, Va is the volume of the acceptor compartment, and S the surfaceof the membrane.

Permselectivity: As described above, the permeability coefficient wascalculated for each cation. By normalizing the permeability coefficientof Na⁺ as 1, the permselectivity for cations M1 and M2 can be calculatedas follows: P_(M1) ^(M2)=P(M2)/P(M1)

Permeability Coefficients of Different Cations Through DifferentMembranes:

Table 14 shows the permeability coefficients of different cations atdifferent membranes. When polymers are more hydrophilic (Polymer D3 andD4 with DBA % 48.5 and 56.1%, respectively), all cations, such as Na⁺,K⁺, Mg²⁺, and Ca²+, are more permeable and their permeabilitycoefficients are comparable to those through a blank dialysis membrane(RC membrane) and reflect the self-diffusivity of the cations. However,with the increasing DBA content in polymer membrane (See Table 20 for D5and D6), the permeability coefficients of different cations decreased ascompared with blank membrane, which means that the hydrophobic nature ofpolymer membrane could make cations less permeable through thehydrophobic barrier.

TABLE 20 Permeability coefficients of cations at different membranes DBAPMg²⁺ PCa²⁺ Polymer ID (mol %) PNa⁺ (cm/sec) PK⁺ (cm/sec) (cm/sec)(cm/sec) D3 48.5 2.41(±0.26)E−4 3.11(±0.34)E−4 6.50(±0.08)E−5 6.0(±0.07)E−5 D4 56.1 4.28(±0.44)E−5 6.11(±0.61)E−4 1.13(±0.11)E−51.04(±0.05)E−5 D5 64.4 4.32(±0.20)E−6 5.79(±3.59)E−6 5.42(±4.11)E−73.32(±3.33)E−7 D6 68.5 1.50(±0.05)E−7 — — —

Another characteristic for the permeability of different cations istheir permselectivity. By normalizing the value of P_(Na+) as 1, thepermselectivity for other cautions can be calculated and the results areshown in Table 21. The permselectivity of P_(Mg)/P_(Na) andP_(Ca)/P_(Na) decreases with the increasing DBA content in polymermembranes, which implies that more hydrophobic polymer membranes mayhave better selectivity for different cations. For a better selectivityfor different cations, two factors should be considered—the chargedensity and the membrane hydrophobicity.

TABLE 21 Polymer P(K⁺)/ P(Ca²⁺)/ P(Mg²⁺)/ P(K⁺)/ ID DBA(%) P(Na⁺) P(Na⁺)P(Na⁺) P(Mg²⁺) D3 48.5 1.29 0.27 0.25 5.16 D4 56.1 1.43 0.26 0.24 5.96D5 64.4 1.34 0.13 0.08 16.75

Example 7 Synthesis of poly-2-fluoroacrylic Acid Beads

Beads are prepared by a direct suspension process where a mixture of2-flouroacrylic methyl ester/divinylbenzene/benzoyl peroxide in a weightratio 90/9/1 are dispersed in water under high shear withpolyvinylalcohol as a suspending agent. The suspension is stirred andheated at 80° C. for 10 hours. The residual monomer is eliminated bysteam stripping. The beads are then filtered and treated with aqueous 3MNaOH to hydrolyze the polymer, then washed, treated with HCL,water-washed, and finally dried to form the desired polyα-fluoroacrylicacid particles. The average bead diameter is 250 microns as measured byMaster Sizer (Malvern UK).

Example 8 Preparation of poly-2-fluoroacrylicacid/core-(DBA-DEAEMA)/Shell Particles

The core-shell particles are prepared by forming a coating of polymer D2on the poly-2-fluoroacrylic acid beads prepared in example 5 using aWurster coater. The shell polymer prepared in example 4 is firstdissolved at 20 wt-% in toluene, and the thus obtained solution thendispersed in water in a 1:4 weight ratio with 2 wt-% based on theorganic phase of CTAB (Hexadecyltrimethyl-Ammonium Bromide) as asurfactant, using a Ultra-Turrax high-shear homogeneizer. The toluene isthen driven off by evaporation under reduced pressure. The averagediameter of the dispersion particles is 0.3 micrometer, as measured byDynamic Light Scattering. The poly-2-fluoroacrylic acid beads arespray-coated with the shell polymer dispersion using a Wurster fluid bedcoater 2″-4″/6″ Portable Unit. The fluidized bed unit is operated sothat an average 5 microns thick coating is deposited on the coreparticles.

Example 9 Preparation of polystyrene sulfonate/core-polvethyleneimineShell Particles with Na+ and K+ Selective-binding Propertie

Procedure for Coating PEI on Dowex Beads

PEI (poly(ethyleneimine), Mw 10,000) and Dowex beads (H-form, X4-200)were purchased from commercial sources. PEI aqueous solutions withdifferent concentrations were prepared by dissolving PEI directly intonanopure water.

Weighed dried Dowex beads were mixed with PEI aqueous solution inlibrary format glass tubes. After a specified reaction time, the tubeswere sealed and centrifuged at 1000 rpm for 15 minutes, the supernatantsolutions were then decanted off. To the beads in each tube was addednanopure water to a total volume of 10 ml and all tubes were sealed andtumbled for 30 minutes. The same tumbling-centrifuging was repeated 3times. The beads were freeze-dried and weighted until a constant weightwas obtained.

The reaction solution composition and gel weight increase are displayedin Table 22.

TABLE 22 Conditions for coating PEI on Dowex beads Dowex Bead PEI PEIReaction Weight Weight Conc. volume time increase (gm) (wt %) (ml)(hours) Coated bead ID (Δwt %) 0.1274 2.5 10 1 DOWEX(2.5 wt-1 h) *0.2223 2.5 10 6 DOWEX(2.5 wt-6 h) 3.1 0.1609 1.5 10 1 DOWEX(2.5 wt-1h) * 0.2407 1.5 10 6 DOWEX(2.5 wt-6 h) 0.9 0.2016 0.5 10 1 DOWEX(2.5wt-1 h) * 0.2347 0.5 10 6 DOWEX(2.5 wt-6 h) * * No weight increase wasobserved.Method for Binding Study

A mixture of NaCl, KCl, MgCl₂, and CaCl₂ was dissolved in a MES buffer(pH6.0) (MES, 2-[N-morpholine]ethanesulfonic acid]. The concentrationfor each cation was determined by IC. The concentrations for Na⁺, K⁺,Mg²⁺, and Ca²⁺ are 26.4 mM, 9.75 mM, 4.75 mM and 4.16 mM respectively.

Weighed dried PEI-coated bead was put into a tube which contains 5-ml ofMES buffer solution of NaCl, KCl, MgCl₂, and CaCl₂. The tube was sealedand tumbled. After a certain period of time as indicated in FIG. 4, thetube was centrifuged. 100 microliter of solution was then taken out fromthe supernatant for IC analysis. The binding amount of PEI coated beadsfor different cations were calculated from the concentration change inthe solution.

The calculation is as follows:

-   Ion bound in beads (mmol/g)=[V×(C₀-C_(t))/{[weight of beads]×1000}-   C₀: initial concentration of metal ion (in mM)-   C_(t): concentration of metal ion after bead binding at a certain    time (t hrs) (in mM)-   V: solution volume (5 ml)-   Weight of beads (gm)

The binding data of different PEI coated beads for different cations areshown in FIG. 4. PEI coated Dowex beads show higher Na⁺ and K⁺ bindingthan the uncoated beads (bare beads). The coated beads show much moreselective binding than bare beads. The thicker the PEI coating (e.g.Dowex (2.5 wt-6 h), coated from 2.5 wt % PEI solution for 6 hours), themore selective for the different cations. The binding kinetic studyshows that the binding of cations equilibrates faster for the thinnercoated beads and bare beads.

Example 10 Polystyrene Sulfonate Beads with Eudragit Shell

Shell material: Eudragit RL100 (Rohm), a copolymer of acrylic andmethacrylic acid esters with 8.85-11.96% cationic ammonio methacrylateunits, 10 wt % in ethanol and 10 wt % triacetin. Core: Lewatit(cross-linked polystyrene sulfonate in sodium form), size −300 μm.

The shell was applied using a FluidAir Wurster coater.

Binding was measured under following conditions:

Donor solution: 50 mM KCl and 50 mM MgCl₂

Bead concentration: 4 mg/ml

Duration: 6 hours

FIG. 5 shows the effect of the shell on Mg²⁺ and K⁺ binding. Withincreasing ratio of shell to core, Mg²⁺ binding decreased and K⁺ bindingincreased. 20 wt % shell coating gave a K⁺ binding capacity of 1.65meq/gm, which is about 3 times higher than for uncoated Dowex.

Example 11 Polystyrene Sulfonate Beads with Benzylated PolyethyleneImine Shell Synthesis of Benzylated Polyethyleneimine (PEI)

To a 250 ml of round bottom flask were charged 15.6 g of PEI (363 mmolof —NH₂) and 125 ml of ethanol, this mixture was magnetically stirreduntil PEI was completely dissolved, then 30 g of NaHCO₃ (FW, 84; 256mmol) and 40 ml of benzyl chloride (363 mmol) were subsequently added.The above mixture was reacted at 55° C. under nitrogen atmosphereovernight. Dichloromomethane was added to the slurry reaction mixture,followed by filtration to remove inorganic salt. The solvent in filtratewas removed by vacuum. Dichloromethane was used again to re-dissolve thereaction product; inorganic salt was further removed by filtration. Thesolvent in the filtrate was removed again under vacuum. Finally, theproduct was triturated in hexane, filtered and washed with hexane, anddried under vacuum. The benzylation degree was 84% as determined by¹HNMR. Similar materials with various degree of benzylation(respectively 20% and 40% for Ben(20) and Ben(40)) were prepared byadjusting the benzyl chloride to PEI ratio.

Benzylated polyethylene imine (Ben-PEI) was coated onto Dowex beads.

The shell was coated using solvent coacervation. The shell Ben(84)-PEIwas dissolved in methanol and water mixture (3:1) at pH of 3. Shell andcore were mixed for 5 minutes and methanol was removed by rotovap (40minutes), isolated, washed, and dried.

Binding was measured under following conditions:

Donor solutions: 50 mM KCl and 50 mM MgCl₂

Bead concentration: 4 mg/ml

Duration: 6 and 24 hours

Results of the binding measurements are shown in FIG. 6. Ben(84)-PEIshowed selective binding for potassium after 6 and 24 hours as revealedby lower Mg²⁺ binding compared to naked beads.

FIG. 7 depicts the stability of Ben(84)-PEI coated Dowex (K) beads underacid conditions representative of the acidic conditions in the stomach.The beads were exposed to pH 2 HCl for 6 hours, isolated, and dried.Binding selectivity was tested for the post-treated beads. Bindingconditions were as follows:

Donor solutions: 50 mM KCl and 50 mM MgCl₂

Bead concentration: 4 mg/ml

Duration: 6 and 24 hours

The coating was stable and binding selectivity was maintained at 6 and24 hours.

Example 12 FAA Beads with Benzylated Polyethylene Imine Shell

The shell was applied on the FAA core by the process of solventcoacervation. The shell, Ben(84)-PEI, was dissolved in methanol andwater mixture (3:1) at pH of 4.5. The shell and core were mixed for 5minutes and methanol was removed by rotovap (40 minutes), isolated,washed, and dried.

Binding was measured under following conditions:

Donor solutions: 50 mM KCl and 50 mM MgCl₂

Bead concentration: 4 mg/ml

Duration: 6 hours

The potassium binding was calculated from actual magnesium uptake andoverall binding capacity of polymer which was 5.74 meq/gm. The resultsare shown in FIG. 8. Increasing the ratio of shell/core caused adecrease in magnesium binding which indicates an increase in potassiumbinding.

Example 13 Coating by Controlled Precipitation Induced by pH Change

The shell comprised of Benzylated PEI, Ben (˜20%); and Ben (˜40%) on aDowex(K) core. Binding was measured in 50 mM KCl and 50 mM MgCl₂.

FIG. 9 shows the results of the binding experiments. Controlledprecipitation method for 40% benzylated PEI shows better coating andthis combination of coating method and materials gives higher bindingselectivity.

Example 14 Membrane Screening of Shell Polymers

Shell polymers were screened by coating a flat membrane via solventcasting and using the coated membrane as the barrier in a diffusioncell, as depicted in FIG. 10. Donor solution was 50 mM 2-[N-morpholino]ethane sulfonic acid (MES) buffer at pH6.5 with 50 mM K⁺ and Mg²⁺.Permeability coefficient was calculated as described in Example 4 above.Cross-linked B-PEI was tested using this method. B-PEI (35 mol %) wascross-linked with 1,4-butanediol diacrylate. The cross-linker wasreacted on the top of dried B-PEI for 4 hours. The screening wasperformed in 50 mM KCl and 50 mM MgCl2 in 50 mM MES buffer. Cross-linker(diacrylate) reacted with B-PEI (35 mol %) membrane. As shown in FIG.11, addition of the cross-linker reduced permeability coefficient andalso showed good selectivity.

Blends of Eudragit RL 100 and RS 100 were also evaluated using themethod of FIG. 10. The results are shown in FIG. 12. Adding RS100 intoRL100 can reduce the permeability and the permselectivity stays in thesame range. Membranes with more than 50 wt % of RS 100 lost selectivity([K⁺] in the same scale, but [Mg²⁺] much higher than other composites).

Example 15 Effects of Bile Acids on K⁺ Binding

Dowex(Li) (˜100 μm) was first coated with PEI aqueous solution. Thesupernatant was removed and the coat was further crosslinked with1,2-Bis-(2-iodoethoxy)-ethane (BIEE). Binding was measured in 50 mM KCland 50 mM of MgCl2, MES buffer, pH 6.5. Bile acids extract used was 2mg/ml (bile extract porcine with 60% bile acids and 40% unknowns, i.e.,free fatty acids, phospholipids, etc.). Time: 6 and 24 hrs and Beadcontent: 4 mg/ml. Results are shown in FIG. 13. Enhanced performance ofthe shell was observed in the presence of bile acids, fatty acids, andlipids.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

It will be apparent to one of ordinary skill in the art that manychanges and modifications can be made thereto without departing from thespirit or scope of the appended claims.

1. A pharmaceutical composition comprising core-shell particles and apharmaceutically acceptable excipient, said core-shell particlescomprises a core component encapsulated in a shell component, said corecomponent comprising a potassium binding polymer, said shell componentcomprising a crosslinked amine functional polymer alkylated withhydrophobic agent(s), said core-shell particles having a capacity forbinding potassium ion in a gastrointestinal tract of an animal subjectand retaining a significant amount of said bound potassium ion during aperiod of residence of the core-shell particles in the gastrointestinaltract of the animal subject.
 2. The pharmaceutical composition of claim1 wherein the core component comprises crosslinked carboxylate,phosphonate, sulfate, sulfonate, sulfamate polymers or combinationsthereof.
 3. A pharmaceutical composition comprising core-shell particlesand a pharmaceutically acceptable excipient, said core-shell particlescomprises a core component encapsulated in a shell component, said corecomponent comprising a potassium binding polymer, said shell componentcomprising a crosslinked amine functional polymer alkylated withhydrophobic agent(s).
 4. The pharmaceutical composition of claim 3wherein the alkylating agents have the formula RX where R is a C₁-C₂₀alkyl, C₁-C₂₀ hydroxy-alkyl, C₆-C₂₀ aralkyl, C₁-C₂₀ alkylammonium, orC₁-C₂₀ alkylamido group and X comprises one or more electrophilicgroups.
 5. The pharmaceutical composition of claim 3 wherein thealkylating agent is an alkyl or alkylaryl group carrying anamine-reactive electrophile.
 6. The pharmaceutical composition of claim3 wherein the alkylating agent is selected from the group consisting ofbenzyl halide and dodecyl halide.
 7. The pharmaceutical composition ofclaim 3 wherein the alkylating agent includes at least two electrophilicgroups X.
 8. The pharmaceutical composition of claim 7 wherein thealkylating agent is selected from the group consisting of di-haloalkane,dihalopolyethylene glycol, and epichlorohydrin.
 9. The pharmaceuticalcomposition of claim 3 wherein the core component comprises crosslinkedcarboxylate, phosphonate, sulfate, sulfonate, sulfamate polymers orcombinations thereof.
 10. The pharmaceutical composition of claim 3wherein the shell thickness is from about 0.002 μm to about 50 μm. 11.The pharmaceutical composition of claim 3 wherein the shell to coreweight ratio is 0.01% to 50%.
 12. The pharmaceutical composition ofclaim 3 wherein the size of the core-shell particle is from about 200 nmto about 2 mm.
 13. The pharmaceutical composition of claim 3 for thetreatment of hyperkalemia, depressed renal synthesis of calcitriol,renal insufficiency, hypertension, chronic heart failure, end stagerenal disease, fluid overload, renal insufficiency, and anabolicmetabolism.
 14. The pharmaceutical composition of claim 3 wherein thepharmaceutically acceptable excipient is one or more pharmaceuticallyacceptable carriers or diluents, and further optionally comprisesadditional therapeutic agents.
 15. A pharmaceutical compositioncomprising core-shell particles and a pharmaceutically acceptableexcipient, said core-shell particles comprises a core componentencapsulated in a shell component, said core component comprising acrosslinked potassium binding polymer, said shell component comprising acrosslinked amine functional polymer alkylated with an alkyl oralkylaryl group.
 16. The pharmaceutical composition of claim 15, thecore component comprising crosslinked carboxylate, phosphonate, sulfate,sulfonate, sulfamate polymers or combinations thereof.
 17. Thepharmaceutical composition of claim 15 wherein the shell thickness isfrom about 0.002 μm to about 50 μm.
 18. The pharmaceutical compositionof claim 15 wherein the alkylating agent is a benzyl halide.
 19. Thepharmaceutical composition of claim 17 wherein the size of thecore-shell particle is from about 200 nm to about 2 mm.
 20. Thepharmaceutical composition of claim 19 wherein the alkylating agent is abenzyl halide.